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THE CUTTING EDGEOF CHEMISTRYA PHARMA MATTERS REPORT.NOVEMBER 2010                       Action-packed chemistry review pro...
The Cutting Edge of Chemistry discloses new ideas and achievements in the                                                 ...
ORGANIC SYNTHESISSCHEME SHOWCASE: MOREEFFICIENT SYNTHESIS OFFERSHOPE OF GlUCOSE CONTROlWITHOUT INSUlINType 2 diabetes mell...
The Pfizer team also points out that this same route provides a                                                           ...
Figure 2. Improved synthetic route for compound 689201                                                                    ...
SCAFFOLDS ON THE MOVE:                                                            THE NEAR AND FAAH OF                    ...
Despite the fact that the three aforementioned series share atrait, the arylurea moiety, the best approach to FAAH inhibit...
Novel chemical scaffolds with biological activity underpin                                                            majo...
PAINKILLERS SHOW SECRET PROMISE IN ALZHEIMER’S                                                                            ...
POTENT SUBSTITUTION LEADS TO POTENTIAL ANTIPSYCHOTICS                                   O       O                The ident...
GSK FINDS BEHAVIORAL ANTAGONISTS                                                                                          ...
SELECTIVE ANTAGONISTS FOR STROKE AND EPILEPSY                                              O                              ...
NEW MOLECULAR MECHANISMS OF ACTIONThe mode of action of any product is key to understanding how to improve on any given de...
THE STARTING LINE                                                                                                         ...
SOURCE DETAILS                                                                                                            ...
SOURCE DETAILS           N                           H                                                                    ...
SOURCE DETAILSORGANIZATION:             LITERATURE:                                       O    N                 O     NEi...
ONE TO WATCH:                                                             DETOX WITH PlASTIC ANTIBODIES                   ...
ADDITIONAL REFERENCES:[1] Preville, C.; Mascitti, V. Syntheses of dioxa-bicyclo [3.2.1]    octane-2,3,4-triol derivative S...
GET THE LATEST CHEMISTRY INSIGHTS                                      Thomson Reuters IntegritySM combines biology, chemi...
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The Cutting Edge of Chemistry, Nov. 2010 -- Pharma Matters Report

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  1. 1. THE CUTTING EDGEOF CHEMISTRYA PHARMA MATTERS REPORT.NOVEMBER 2010 Action-packed chemistry review providing insight into the latest synthesis schemes, scaffolds, mechanisms of action and new structures advancing drug discovery and development.
  2. 2. The Cutting Edge of Chemistry discloses new ideas and achievements in the biomedical research field with the chemist’s perspective in mind and is a recently launched addition to the Pharma Matters report series. The report has been organized into sections that delineate essential aspects of the search for better and safer drugs. IN THIS ISSUE Thomson Reuters Integrity covers over 300 scientific conferences and meetings each year. Our scientific reporters, who attend these meetings, record the key findings, curating and indexing the information within Integrity. This report highlights content from Integrity covering some of the biggest meetings over the past few months, including the 240th ACS National Meeting, the 50th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) and the 9th International Meeting of the International Society for the Study of Xenobiotics (ISSX). 1 ORGANIC SYNTHESIS SCHEME SHOWCASE The sodium glucose cotransporter 2 represents a possible target for antidiabetic drugs, according to recent research. Novel drug leads derived from natural products are discussed. 4 SCAFFOLDS ON THE MOVE Avoiding side effects that include dysphoria, dizziness and motor coordination problems in endocannabinoid manipulation might lead to an improved approach to pain relief and nausea reduction in cancer patients and people with multiple sclerosis. In this section, we discuss recent news on FAAH inhibition. 11 NEW MOLECULAR MECHANISMS OF ACTION GTPase inhibitors, bacterial regulators and drugs for ischemia and hyperlipidemia all feature new modes of action. We showcase a range of fascinating compounds in this issue. 12 THE STARTING LINE Integrity features The Starting Line, which pinpoints new molecular entities (NMEs) ready to progress into the R&D area. In this report we look at some highlights from the conferences held over the past few months. 16 ONE TO WATCH Mice bloodstream detoxified with a plastic antibody: a proof-of-concept of their therapeutic potential.THOMSON REUTERS INTEGRITYSM: EMPOWERING YOUR RESEARCH
  3. 3. ORGANIC SYNTHESISSCHEME SHOWCASE: MOREEFFICIENT SYNTHESIS OFFERSHOPE OF GlUCOSE CONTROlWITHOUT INSUlINType 2 diabetes mellitus is a growing health problem worldwideand the condition is a sharp focus of much research in thepharmaceutical industry. The sodium glucose cotransporter 2(SGlT2) has been identified as a possible target for antidiabeticdrugs. Inhibiting this protein would slow glucose reuptake inthe kidneys and potentially allow control of hyperglycemia in aglucose-dependent way without recourse to modulating insulin.A putative lead for drug discovery in this area emerged in theform of an O-aryl glucoside natural product known as phlorizin,a toxic dihydrochalcones flavonoid found in the bark of commonfruit trees, such as pear, apple and cherry. Its toxicity is relatedto its nonselective ability to inhibit SGlT1 and SGlT2, whichsuggests that more selective derivatives might be useful inglucose transport inhibition.Indeed, several structurally akin O-aryl and C-aryl glucosidesare currently in clinical trials. With a differential trait fromother members of the C-aryl glucoside series, an ether bridge,compound 689201 in Integrity, was discussed in the ORGNsessions of the 240th National Meeting of the AmericanChemical Society [1]. Vincent Mascitti and Cathy Préville of PfizerGlobal Research and Development, in Groton, Connecticut,presented the evolution of the synthetic approach to thecompound along the development pathway (also later outlinedin Org Lett 2010, 12(13): 2940).The team’s original route [Fig. 1] relied on an acyclic Weinrebamide as an advanced versatile intermediate, which allowedfor the convenient preparation of analogs in the early stages ofdevelopment. However, with a 0.3% yield over 13 linear steps anda final HPlC separation of diastereomers, this approach was notwell suited for large-scale synthesis, the team explains.A more efficient synthetic route is now envisaged [Fig. 2] for thecompound, in phase II clinical trials. The new approach standsout for exploiting pseudo C2-symmetry in the identification of thediacetone-D-mannofuranose as starting material.The aldehyde derived from this carbohydrate precursorundergoes addition with the convenient dithiane carbanionto afford a single diastereomer. From this point, the newstereoselective route offers a 26% yield over five linear steps,“which constitutes a major improvement over the original route,”the team says. PHARMA MATTERS | THE CUTTING EDGE OF CHEMISTRY 1
  4. 4. The Pfizer team also points out that this same route provides a quick entry point to C1- and C5-substituted dioxabicyclo[3.2.1] octane-2,3,4-triol derivatives that might also have useful biological activity. INTEGRITY ENTRY NUMBER: 689201 Figure 1. Original synthetic route for compound 689201 O OH O O HO HO CH2=CHCH2OH HO OH CF3SO3H HO OH CH2 OH OH (I) (II) Ph3CCl, Et3N O O O O HO CH2 TrtO 1) PhCH2Cl or PhCH2Br, NaH BnO OBn HO OH CH2 2) H2SO4 OBn OH (IV) (III) 1) (COCl)2, DMSO, Et3N 2) HCHO, NaOH HO PMBO O O O O HO CH2 PMBO BnO OBn BnO OBn CH2 PMB-Br, NaH OBn OBn (V) (VI) PdCl2 PMBO PMBO O O O OH PMBO (COCl)2, DMSO PMBO OBn Et3N OBn BnO BnO OBn OBn (VIIII) (VII) MeNHOMe·HCl Me3Al PMBO Cl O CH3 OBn O PMBO OMe N Br OH OBn OBn CH3 (X) (IX) BuLi -78°C Cl O CH3 PMBO OH O PMBO BnO OBn TFA, PhOMe OBn (XI) Cl O CH3 O O HO BnO OBn OBn (XII) 1) HCOOH, Pd 2) preparative HPLC Cl O CH3 O O HO HO OH OH2 THOMSON REUTERS INTEGRITYSM: EMPOWERING YOUR RESEARCH
  5. 5. Figure 2. Improved synthetic route for compound 689201 O TBDMSO O Cl O CH3 H S O O S H3C CH3 (I) (II) BuLi Cl O CH3 S S TBDMSO O OH O O H3C CH3 (III) TBAF Cl O CH3 S S HO O OH O O H3C CH3 (IV) HCHO K2CO3 Cl O CH3 S S HO O OH HO O O H3C CH3 (V) NaBH4 Cl O CH3 HO HO S O S H3C O OH H3C OH (VI) TFA Cl O CH3 O O HO HO OH OH PHARMA MATTERS | THE CUTTING EDGE OF CHEMISTRY 3
  6. 6. SCAFFOLDS ON THE MOVE: THE NEAR AND FAAH OF ENDOCANNABINOID MANIPUlATION The manipulation of endocannabinoid degradation through fatty acid amide hydrolase (FAAH) inhibition was a focus of discussion at the 240th National Meeting of the American Chemical Society in August 2010. Cannabinoid 1 (CB1) agonists have already been approved by regulatory agencies for reducing nausea and pain in cancer and multiple sclerosis patients. Unfortunately, these agents have side effects, including dysphoria, dizziness and motor coordination problems. FAAH is a member of the serine hydrolase family of enzymes which catabolizes the endogenous cannabinoid ligand (endocannabinoid) anandamide (AEA). AEA has been shown to produce analgesic effects in vivo, with none of the side effects observed when targeting the CB1 receptor exogenously [2]. Thus, FAAH inhibition could allow for a more selective approach to cannabinoid-mediated analgesia. The pharmacological profile of FAAH inhibitors can be different according to their mode of action. As a general observation, reversible FAAH inhibitors exhibit very satisfactory selectivity indexes. However, their efficacy is usually only partial, presumably because they are metabolized rapidly. In contrast, irreversible FAAH inhibition tends to correlate with high in vivo efficacy, although selectivity might be compromised, given that more than 200 serine hydrolases are encoded in the human proteome [3]. During the last ACS National Meeting session, three well-known pharmaceutical companies, Amgen, Johnson & Johnson and Pfizer, commented on their strategies to FAAH inhibition. The Pfizer team presented a series of piperidine ureas [Featured Scaffold 1], and argued that they act irreversibly at the enzyme, by covalently binding the nucleophilic serine 241 in the active site. Notably, the compounds were proven to exhibit an outstanding selectivity over other serine hydrolases. A representative of this class, currently in phase II clinical trials, is PF-04457845. Johnson & Johnson in San Diego similarly described the discovery of a novel class of piperidine urea FAAH inhibitors [Featured Scaffold 2], exemplified by compound 707111 in Integrity, and discussed structure-activity relationships (SARs) as well as results in preclinical pain models. Finally, Amgen researchers in South San Francisco were aiming at the design of reversible noncovalent binding FAAH inhibitors [Featured Scaffold 3]. By combining high-throughput screening and rational design with this mechanistic prerequisite, they identified a preliminary set of sterically constrained cyclic ureas. The mode of action was confirmed by co-crystallization studies. This starting point was subsequently refined by SAR studies, leading to the exemplified compound 656203 in Integrity.4 THOMSON REUTERS INTEGRITYSM: EMPOWERING YOUR RESEARCH
  7. 7. Despite the fact that the three aforementioned series share atrait, the arylurea moiety, the best approach to FAAH inhibitionis still a matter of debate.FEATURED SCAFFOLD 1THERAPEUTIC GROUP: MOST RECENT SOURCE: F F ONon-Opioid Analgesics Johnson, D. F N N N N Discovery of PF-04457845, an H irreversible FAAH inhibitor with N O exquisite selectivity. 240th ACS Natl Meet (August 22– 26, Boston) 2010, Abst MEDI 500.ORGANIZATION: INTEGRITY ENTRY NUMBER:Pfizer 640867FEATURED SCAFFOLD 2THERAPEUTIC GROUP: MOST RECENT SOURCE: ONon-Opioid Analgesics Tichenor, M.S.; Keith, J.M.; Cl N N N Apodaca, R.l.; Xiao, W.; et al. H N Inhibitors of fatty acid amide O hydrolase (FAAH): SAR and results in pre-clinical pain models. 240th ACS Natl Meet (August 22– 26, Boston) 2010, Abst MEDI 499.ORGANIZATION: INTEGRITY ENTRY NUMBER:Johnson & Johnson 707111Pharmaceutical R&DFEATURED SCAFFOLD 3 NH2THERAPEUTIC GROUP: MOST RECENT SOURCE: NNon-Opioid Analgesics Gustin, D.J.; li, Y.; Hedberg, C.; N N Min, X.; et al. H3C N N N Discovery of a novel series of potent, non-covalent fatty acid amide O F hydrolase (FAAH) inhibitors through rational design. 240th ACS Natl Meet (August 22– 26, Boston) 2010, Abst MEDI 498.ORGANIZATION: INTEGRITY ENTRY NUMBER:Amgen 656203 PHARMA MATTERS | THE CUTTING EDGE OF CHEMISTRY 5
  8. 8. Novel chemical scaffolds with biological activity underpin major advances in medicinal chemistry. Showcased here are some of the latest scaffolds within drugs for a wide range of therapeutic areas. 2-AMINOIMIDAZOLE MOIETY OFFERS ARGINASE ATTACK O An SAR analysis by David Christianson of the University of Pennsylvania and H2N OH NH2 colleagues demonstrates that the 2-aminoimidazole group can target metal coordination and hydrogen bond interactions in the active site of arginase, a N N key metalloenzyme of the urea cycle. Targeting this enzyme, which converts l-arginine into l-ornithine and urea is promising in the management of diseases in which l-arginine homeostasis goes awry, including asthma, cardiovascular diseases and erectile dysfunction. New arginase inhibitors should emerge from this work that exhibit alternative and improved pharmacokinetic profiles. THERAPEUTIC GROUP: MOST RECENT SOURCE: Antiallergy/Antiasthmatic Drugs Ilies, M.; Di Costanzo, l.; North, M.l.; Scott, J.A.; Christianson, D.W. 2-Aminoimidazole amino acids as inhibitors of the binuclear manganese metalloenzyme human arginase I. J Med Chem 2010, 53(10): 4266. ORGANIZATION: INTEGRITY ENTRY NUMBER: University of Pennsylvania 698475 University of Toronto NONSTEROIDAL PROSTATE THERAPY SIDESTEPS RESISTANCE A nonsteroidal benzopyran-containing androgen receptor antagonist could find utility in treating resistant forms of prostate cancer, according O to researchers at Seoul National University. They carried out a medium- HO throughput screening exercise on 2000 drug-like small molecules to N identify the scaffold, which competes with the endogenous agonist O dihydrotestosterone. The screen was a cell-based reporter gene assay and HO O activity was confirmed by western blot analysis, RT-PCR and in vitro cellular proliferation assay. The new lead holds promise of overcoming the problems of resistance seen with flutamide and bicalutamide in long-term use by side-stepping their well-known substructure. THERAPEUTIC GROUP: MOST RECENT SOURCE: Prostate Cancer Therapy Oh, S.; Nam, H.J.; Park, J.; Beak, S.H.; Park, S.B. Development of a benzopyran- containing androgen receptor antagonist to treat antiandrogen- resistant prostate cancer. ChemMedChem 2010, 5(4): 529. ORGANIZATION: INTEGRITY ENTRY NUMBER: Seoul National University 6998246 THOMSON REUTERS INTEGRITYSM: EMPOWERING YOUR RESEARCH
  9. 9. PAINKILLERS SHOW SECRET PROMISE IN ALZHEIMER’S OResults from in vivo models suggest that the combined action of γ-secretase O N Smodulators and peroxisome proliferator-activated receptor γ agonists has OHpotential in the treatment of Alzheimer’s disease. Researchers from Roche N CH3now disclose the first drug-like compounds that exhibit dual activity overthe two targets. SAR studies around the initial hit, 2-(bis(phenethoxy) Opyrimidine-2-ylthio)hexanoic acid, indicated that the carboxylic acidmoiety is crucial for both activities, and that the initial butyl group at thestereocenter has the optimal length. The exemplified compound, withcyclohexyl substitution at the phenyl ring, was the most active compound(IC50(Aβ42) = 5.1 μM and EC50(PPAR-γ) = 6.6 μM). Importantly, it was shownthat it did not produce impairment of NOTCH processing and signaling overthe tested concentration range (5-40 μM).THERAPEUTIC GROUP: MOST RECENT SOURCE:Alzheimer’s Dementia, Treatment of Hieke, M.; Ness, J.; Steri, R.; et al. Design, synthesis, and biological evaluation of a novel class of gamma-secretase modulators with PPARgamma activity. J Med Chem 2010, 53(12): 4691.ORGANIZATION: INTEGRITY ENTRY NUMBER:Roche 701189SMALL SCREEN REVEALS NOVEL CANCER INHIBITOR HResearchers in China have rapidly synthesized a focused library of 350 HO N CH2furanopyrimidines in parallel reactors and then screened them alternatively Ofor Aurora and epidermal growth factor receptor (EGFR) kinase inhibitory NHactivity. Out of three promising candidates, resynthesis confirmed one hit Nas a potent EGFR kinase inhibitor, and devoid of Aurora kinase inhibition.Docking results with this hit suggest that the furanopyrimidine ring oxygen N Oforms the required hinge binding interaction with the Met769 hinge residue,while the three phenyl rings form extensive hydrophobic interactions withthe surrounding residues. Introduction of a Michael acceptor group gaverise to a marked improvement in activity. The novel lead thus obtainedcould hold promise in the development of an alternative cancer therapy forgefitinib-resistant EGFR-overexpressing tumors.THERAPEUTIC GROUP: MOST RECENT SOURCE:Oncolytic Drugs Coumar, M.S.; Chu, C.Y.; lin, C.W.; et al. Fast-forwarding hit to lead: Aurora and epidermal growth factor receptor kinase inhibitor lead identification. J Med Chem 2010, 53(13): 4980.ORGANIZATION: INTEGRITY ENTRY NUMBER:Chung Yuan Christian University 702179National Chiao Tung UniversityNational Health ResearchInstitutes (TW)National Tsing Hua University PHARMA MATTERS | THE CUTTING EDGE OF CHEMISTRY 7
  10. 10. POTENT SUBSTITUTION LEADS TO POTENTIAL ANTIPSYCHOTICS O O The identification of N-(2-(azepan-1-yl)-2-phenylethyl)- N S benzenesulfonamides as novel inhibitors of glycine transporter H 1 (GlyT1) offers new hope for antipsychotic agents for treating O N F H3C schizophrenia. Employing a pharmacophore-encoded virtual screening, F F a benzenesulfonamide resulted as the most potent hit. Subsequent SAR studies revealed that this moiety provided the best balance between potency and solubility. Exchanging the piperidine ring in the hit by the homologous azepane ring gave a 3-fold increase in potency, while other modifications from the original (other ring sizes, ring truncation or heteroatom variation) proved detrimental for activity. THERAPEUTIC GROUP: MOST RECENT SOURCE: Antipsychotic Drugs Varnes, J.G.; Forst, J.M.; Hoerter, T.N.; et al. Identification of N-(2-(azepan-1-yl)-2-phenylethyl)- benzenesulfonamides as novel inhibitors of GlyT1. Bioorg Med Chem Lett 2010, 20(16): 4878. ORGANIZATION: INTEGRITY ENTRY NUMBER: AstraZeneca 704339 RHEUMATOID ARTHRITIS INHIBITORS, IN THE NIK OF TIME O Inhibition of NF-κB-inducing kinase (NIK) represents an important area NH of research in rheumatoid arthritis. Until now, however, very few NIK inhibitors have been reported. By applying a carefully designed set of O sequential restrictions, scientists in Belgium narrowed down an initial small-molecule pool of 8 million compounds to a final set of 49 candidates for in vitro screening. Two new fragments, 4H-isoquinoline-1,3-dione and 2,7-napthyridine-1,3,6,8-tetrone, were thus identified, exhibiting an IC50 of 51 and 90 µM, respectively, in a radiometric protein assay. Analogs of the former scaffold have previously been reported as having activity against other kinases. This work is still in progress and other analogs are being investigated for NIK activity. THERAPEUTIC GROUP: MOST RECENT SOURCE: Rheumatoid Arthritis, Treatment of Mortier, J.; Masereel, B.; Remouchamps, C.; Ganeff, C.; Piette, J.; Frederick, R. NF-kappaB inducing kinase (NIK) inhibitors: Identification of new scaffolds using virtual screening. Bioorg Med Chem Lett 2010, 20(15): 4515. ORGANIZATION: INTEGRITY ENTRY NUMBER: Fac Univ Notre-Dame de la Paix — 703714 Namur CHU liège8 THOMSON REUTERS INTEGRITYSM: EMPOWERING YOUR RESEARCH
  11. 11. GSK FINDS BEHAVIORAL ANTAGONISTS HGlaxoSmithKline scientists in Italy have identified two new series of potent H3C N O Oantagonists of vasopressin-1b receptor in their proprietary compound CH3collection. The compounds have submicromolar potency and high F N F O Nselectivity. Neither the pyrrole-pyrazinone- nor the pyrazole-pyrazinone- N F Ntype compounds interfere with the V1a, V2 or oxytocin receptors, and allhave good central nervous system penetration. A selected 3-trifluoromethyl- F4-fluorophenyl-substituted derivative from the pyrazole-pyrazinone serieswas further studied in vivo, exhibiting an encouraging pharmacokineticprofile and good CNS penetration in the rat. The compounds could havepotential in a range of diseases, such as behavioral problems, anxiety anddepression.THERAPEUTIC GROUP: MOST RECENT SOURCE:Anxiolytics; Antidepressants Arban, R.; Bianchi, F.; Buson, A.; et al. Pyrrolo[1,2-a]pyrazine and pyrazolo[1,5-a]pyrazine: Novel, potent, and selective series of Vasopressin1b receptor antagonists. Bioorg Med Chem Lett 2010, 20(17): 5044.ORGANIZATION: INTEGRITY ENTRY NUMBER:GlaxoSmithKline 708330TREATING ALZHEIMER’S WITHOUT ANXIETY OResearchers in Japan have used high-throughput screening to identifypyrido[2,3-d]pyrimidine-4(1H)-one derivatives as α5GABAA ligands. NThis receptor is highly expressed in the hippocampus and so is thought to N N Nplay a role in learning and memory. ligands for the receptor might thereforedemonstrate benefits in treating problems of cognition, such as those N N CH3seen in Alzheimer’s disease. These new modulators are promising not onlybecause of their in vivo activity at low dose but because they show none ofthe anxiogenic or convulsant effects associated with other less-selectivecompounds acting at α5GABAA.THERAPEUTIC GROUP: MOST RECENT SOURCE:Alzheimer’s Disease, Treatment of Sugawara, M.; Danjo, T.; Nakajima, T.; Uchida, S.; et al. Pyrido[2,3-d] pyridine -4(1H)-ones: A novel class of gaba-a alfa5 receptor inverse agonists. Drugs Fut 2010, 35(Suppl. A): Abst PC.380.ORGANIZATION: INTEGRITY ENTRY NUMBER:Kyowa Hakko Kirin 697329 PHARMA MATTERS | THE CUTTING EDGE OF CHEMISTRY 9
  12. 12. SELECTIVE ANTAGONISTS FOR STROKE AND EPILEPSY O Quinazolin-4-one derivatives represents a novel class of noncompetitive O OH NR2C/D subunit-selective N-methyl-D-aspartate (NMDA) receptor I antagonists according to work in the US and Denmark. The compounds N contain the (E)-3-phenyl-2-styrylquinazolin-4(3H)-one backbone and inhibit N recombinant NMDA receptor function, and were identified after completion of a fluorescence-based screen of 83,880 compounds. They could represent NO2 some of the first compounds for neurological disorders that are more than tenfold selective for their NR2C/D-containing NMDA target receptor. The compounds therefore have potential in stroke treatment and epilepsy. THERAPEUTIC GROUP: MOST RECENT SOURCE: Stroke, Treatment of; Mosley, C.A.; Acker, T.M.; Antiepileptic Drug Hansen, K.B.; et al. Quinazolin-4-one derivatives: A novel class of noncompetitive NR2C/D subunit-selective n-methyl- d-aspartate receptor antagonists. J Med Chem 2010, 53(15): 5476. ORGANIZATION: INTEGRITY ENTRY NUMBER: Emory University 705078 University of Copenhagen10 THOMSON REUTERS INTEGRITYSM: EMPOWERING YOUR RESEARCH
  13. 13. NEW MOLECULAR MECHANISMS OF ACTIONThe mode of action of any product is key to understanding how to improve on any given design and how tofind more potent leads with fewer potential side effects. GTPase inhibitors, bacterial regulators and drugs forischemia and hyperlipidemia all feature new modes of action. We showcase a range of fascinating compoundsin this issue. O O F O F F F O N N N H H F O F HO O NH HN O OH O N N N OH OH H3C N H N N Br N S N N N O N N CH3DYNAMIN GTPASE BACTERIAL DEATH-ASSOCIATED MONOACYLGLYCEROLINHIBITORS TRANSCRIPTIONAL PROTEIN KINASE (DAPK) O-ACYLTRANSFERASE 2 REGULATORY PROTEIN INHIBITORS (MGAT2) INHIBITORS WAIR INHIBITORSMAIN RELATED CONDITIONS: MAIN RELATED CONDITIONS: MAIN RELATED CONDITIONS: MAIN RELATED CONDITIONS:Infections Infection, bacterial Ischemia Hyperlipidemia; Diabetes; ObesityORGANIZATION: ORGANIZATION: ORGANIZATION: ORGANIZATION:University of Newcastle, Kirin Holdings PharmaDesign BanyuAustralia NB Health laboratory (NBHl)University of Sydney DRUG NAME: Walrycin BINTEGRITY ENTRY NUMBER: INTEGRITY ENTRY NUMBER: INTEGRITY ENTRY NUMBER: INTEGRITY ENTRY NUMBER:698429 699525 695636 707130 O O N O H3C N O O2N N OH N H F O S CH3 OELECTRONEURAL THERMOREGULATORYPOTASSIUM-CHLORIDE PROTEIN LCRF INHIBITORSCOTRANSPORTER 2 (KCC2)INHIBITORSMAIN RELATED CONDITIONS: MAIN RELATED CONDITIONS:Epilepsy Infection, bacterialORGANIZATION: ORGANIZATION:UCB Paratek PharmaceuticalsINTEGRITY ENTRY NUMBER: INTEGRITY ENTRY NUMBER:696970 449263 PHARMA MATTERS | THE CUTTING EDGE OF CHEMISTRY 11
  14. 14. THE STARTING LINE Thomson Reuters Integrity features The Starting Line, which pinpoints new molecular entities (NMEs) ready to progress into the R&D area. The Cutting Edge of Chemistry highlights a selection of these compounds. In this issue we look at some highlights from the conferences held over the past few months. SOURCE DETAILS H O OH CH3 N NH2 O OH O O H3C CH3 O CH3 O NH O ORGANIZATION: LITERATURE: H2N N H H N N H H H N N H H N N H H N N H H N OH Creighton University Kovalszky, I.; Surmacz, E.; I O O CH3 H O H3C CH3 O CH3 O OH O Semmelweis University Scolaro, l.; et al. N CH3HO O OH O Medical School leptin-based glycopeptide induces I OH OH Temple University weight loss and simultaneously PRODUCT: restores fertility in animal models. E1/Aca Diabetes Obes Metab 2010, 12(5): 393. CONDITION: Obesity MECHANISM OF ACTION: leptin Receptor (OBR) Agonists INTEGRITY ENTRY NUMBER: 701707 O NH2 NH2 ORGANIZATION: LITERATURE: Novartis Chen, Y.l.; Yin, Z.; N PRODUCT: lakshminarayana, S.B.; et al. N N NITD-203 Inhibition of dengue virus O RNA synthesis by an adenosine H3C O CONDITION: nucleoside. O Infection, dengue virus Antimicrob Agents Chemother 2010, CH3 O CH OH MECHANISM OF ACTION: 54(7): 2932. H3C O Dengue Virus RNA-Directed RNA Chen, Y.l.; Yin, Z.; CH3 Polymerase (NS5) Inhibitors Duraiswamy, J.; et al. INTEGRITY ENTRY NUMBER: Inhibition of dengue virus by an ester 701621 prodrug of an adenosine analog. Antimicrob Agents Chemother 2010, 54(8): 3255. H N ORGANIZATION: LITERATURE: lundbeck Sams, A.G.; Hentzer, M.; Mikkelsen, N O PRODUCT: G.K.; larsen, K.; et al. N O lu-AE51090 Discovery of N-{1-[3-(3-Oxo-2,3- dihydrobenzo[1,4]oxazin-4-yl)propyl] CONDITION: piperidin-4-yl}-2-phenylacetamide O Dementia, Alzheimer’s type (lu AE51090): An allosteric Schizophrenia muscarinic M1 receptor agonist MECHANISM OF ACTION: with unprecedented selectivity and Muscarinic M1 Agonists procognitive potential. INTEGRITY ENTRY NUMBER: J Med Chem 2010, 53(17): 6386. 70449312 THOMSON REUTERS INTEGRITYSM: EMPOWERING YOUR RESEARCH
  15. 15. SOURCE DETAILS SORGANIZATION: LITERATURE: HNGlaxoSmithKline Barfoot, C.W.; Brown, P.; Dabbs, S.; N OPRODUCT: Davies, D.T.; Hennessy, A.J.;GSK-299423 Miles, T.J. N The design of efficient and selective .2HClCONDITION: routes to pyridyl analogues ofInfection, bacterial 2,3-dihydro-1,4-benzodioxin-6- O CN H3CMECHANISM OF ACTION: carbaldehyde.DNA Gyrase Inhibitors Tetrahedron Lett 2010, 51(38): 5038. NINTEGRITY ENTRY NUMBER: Bax, B.D.; Chan, P.F.; Eggleston, D.S;705655 Fosberry, A.; et al. Type IIA topoisomerase inhibition by a new class of antibacterial agents. Nature 2010, 466(7309): 935. H3C CH3ORGANIZATION: LITERATURE: O S CH3NeuroGenetic Pharmaceuticals Cheng, S.; Comer, D.; Mao, l.;PRODUCT: Pleynet, D.; et al. N N 2-Aminothiazoles derivatives HNGP-328 H3C CH3 as potent gamma-secretase NCONDITION: modulators. N ODementia, Alzheimer’s type 240th ACS Natl Meet (August CH3MECHANISM OF ACTION: 22–26, Boston) 2010, Abst MEDI 1.Antiamyloidogenic Agentsgamma-Secretase ModulatorsINTEGRITY ENTRY NUMBER:706409 H 3C OORGANIZATION: LITERATURE: N NPharmasset Sofia, M.J.; Bao, D.; Chang, W.; Chun, B.-K.; et al. H2N N NPRODUCT:PSI-353661 Discovery of PSI-352938 and CH3 O PSI-353661: Purine nucleotide H 3C O P OCONDITION: prodrugs for the treatment of HCV. N H O CH3Hepatitis C (HCV) 240th ACS Natl Meet (August CH3 O O HO FMECHANISM OF ACTION: 22–26, Boston) 2010, Abst MEDI 19.RNA-Directed RNA Polymerase Chang, W.; Bao, D.; Chun, B.-K.;(NS5B) Inhibitors Nagarathnam, D.; et al.INTEGRITY ENTRY NUMBER: Discovery of PSI-353661: A novel703838 purine nucleotide prodrug with improved in vitro potency for the treatment of HCV infection. 240th ACS Natl Meet (August 22– 26, Boston) 2010, Abst MEDI 124. NORGANIZATION: LITERATURE:Albany Molecular Research (AMRI) Manning, D.D.; Cioffi, C.l.; O NCelentyx Ryan, K.N.; Usyatinsky, A.; et al.CONDITION: Novel 5-HT3 receptor partialIrritable bowel syndrome agonists for the potential treatment N of irritable bowel syndrome. NMECHANISM OF ACTION: Drugs Fut 2010, 35(Suppl. A): CH35-HT3 Partial Agonists Abst PC.073.INTEGRITY ENTRY NUMBER:707628 PHARMA MATTERS | THE CUTTING EDGE OF CHEMISTRY 13
  16. 16. SOURCE DETAILS N H ORGANIZATION: LITERATURE: N N N CH3 Array BioPharma liederer, B.M.; Baumgardner, M.; O O Genentech Dean, B.; et al.F O HN PRODUCT: Investigation of metabolism in mice, F F GNE-A rats, monkeys, dogs and humans N of a novel met kinase inhibitor for N N H CONDITION: species selection for preclinical Cancer toxicology studies. MECHANISM OF ACTION: 9th Int ISSX Meet (September 4–8, HGFR (MET; c-Met) Inhibitors Istanbul) 2010, Abst P347. INTEGRITY ENTRY NUMBER: liederer, B.M.; Dinkel, V.; Gaudino, 707607 J.; Gopaul, S.; le, H.; liu, X.; Sutherlin, D.; Wong, S.; Khojasteh, C. Influence of fluorine substitution at the C-3 position on oxidative metabolism of N-ethylpiperidine analogs. 9th Int ISSX Meet (September 4–8, Istanbul) 2010, Abst P346. liederer, B.M.; Berezhkovskiy, l.M.; Dean, B.; Dinkel, V.; et al. Preclinical profiling, prediction of human pharmacokinetics and pharmacokinetic-pharmacodynamic modeling of a potent and selective met kinase inhibitor. 9th Int ISSX Meet (September 4–8, Istanbul) 2010, Abst P427. O ORGANIZATION: LITERATURE: O H legoChem Biosciences Oh, T.; Song, T.; Cho, Y.; lee, H.; F N N O CH3 PRODUCT: Woo, S.; et al. O lCB01-577 In vitro anti-tuberculous activity of N new oxazolidinones against drug O CONDITION: resistance tuberculosis. N Tuberculosis 50th Intersci Conf Antimicrob Agents INTEGRITY ENTRY NUMBER: Chemother (ICAAC) (September 708705 12–15, Boston) 2010, Abst F1-2144.14 THOMSON REUTERS INTEGRITYSM: EMPOWERING YOUR RESEARCH
  17. 17. SOURCE DETAILSORGANIZATION: LITERATURE: O N O NEisai Miyazaki, M.; Horii, T.;PRODUCT: Hata, K.; Watanabe, N.E-1210 In vitro antifungal activity of E1210: A N NH2 novel antifungal with activity againstCONDITION: clinically important yeasts andInfection, fungal moulds.INTEGRITY ENTRY NUMBER: 50th Intersci Conf Antimicrob Agents666392 Chemother (ICAAC) (September 12–15, Boston) 2010, Abst F1-840. Watanabe, N.; Horii, T.; Miyazaki, M.; Hata, K. E1210, a new broad-spectrum antifungal, inhibits glycosylphosphatidylinositol (GPI) biosynthesis and effects candida albicans cell characteristics. 50th Intersci Conf Antimicrob Agents Chemother (ICAAC) (September 12–15, Boston) 2010, Abst F1-841. Hata, K.; Miyazaki, M.; Horii, T.; Watanabe, N. Efficacy of E1210, a new broad-spectrum antifungal, in murine models of oropharyngeal candidiasis, disseminated candidiasis, and pulmonary aspergillosis. 50th Intersci Conf Antimicrob Agents Chemother (ICAAC) (September 12–15, Boston) 2010, Abst F1-842. Horii, T.; Okubo, M.; Miyazaki, M.; Hata, K.; et al. In vivo pharmacodynamic correlates of success for E1210 treatment of disseminated candidiasis. 50th Intersci Conf Antimicrob Agents Chemother (ICAAC) (September 12–15, Boston) 2010, Abst F1-843. Okubo, M.; Toritsuka, N.; Horii, T.; Hata, K.; et al. Preclinical pharmacokinetics and toxicology of E1210, a new broad- spectrum antifungal. 50th Intersci Conf Antimicrob Agents Chemother (ICAAC) (September 12–15, Boston) 2010, Abst F1-844. PHARMA MATTERS | THE CUTTING EDGE OF CHEMISTRY 15
  18. 18. ONE TO WATCH: DETOX WITH PlASTIC ANTIBODIES Plastic antibody nanoparticles could be synthesized to specifically target almost any blood-borne toxin and so be used to create a detoxifying serum for removing bacterial toxins or the noxious agents in various venoms. Now, Kenneth Shea of the University of California Irvine and colleagues in the US and Japan have successfully provided proof-of-concept for the detoxifying potential of a plastic antibody in living mice [4]. The team demonstrated that their plastic antibody (705109 in Integrity) can capture and clear a target peptide toxin, melittin, from the bloodstream, reducing mortality in the mice and diminishing peripheral toxic symptoms significantly. Plastic antibodies mimic natural antibodies by targeting molecules with high affinity by interaction of their complementary surfaces. They are usually made by molecular imprinting of a monomer solution containing small amounts of the target molecule during polymerization, which results in a polymer network pocked with complementary binding sites for the target. Shea and colleagues’ synthesis of a novel nanoparticle (NP) plastic antibody combines molecular imprinted polymers (MIP) plastic antibody production and monomer optimization strategy [5]. “We have developed methods for synthesizing protein- sized polymer particles with a binding affinity and selectivity comparable to those of natural antibodies by combining MIP nanoparticle synthesis with a functional monomer optimization strategy,” Shea explains. The first step involved testing a small library of nanoparticles preselected by virtue of their a priori complementary structure relative to the biological target. “The affinity of each NP for the biological target is evaluated, and the composition of subsequent NP generations is adjusted to enhance the specificity,” Shea and colleagues add. At each cycle the refined monomers were polymerized with the imprinting target, peptide or epitope, to produce plastic antibody nanoparticles, until the binding affinity, selectivity and particle size was ultimately comparable to that of natural antibodies. Shea adds that, “Coupled with their biocompatibility and nontoxic characteristics, plastic antibodies offer the potential for neutralizing a wide range of biomacromolecules in vivo.” INTEGRITY ENTRY NUMBER: 70510916 THOMSON REUTERS INTEGRITYSM: EMPOWERING YOUR RESEARCH
  19. 19. ADDITIONAL REFERENCES:[1] Preville, C.; Mascitti, V. Syntheses of dioxa-bicyclo [3.2.1] octane-2,3,4-triol derivative SGlT2 inhibitors. 240th ACS Natl Meet (August 22–26, Boston) 2010, Abst ORGN 930.[2] Walker, J.M.; et al. Pain modulation by release of the endogenous cannabinoid anandamide. Proc Natl Acad Sci USA 1999, 96: 12198.[3] Ahn, K.; Stevens, R.C.; Cravatt, B.F.; et al. Discovery and characterization of a highly selective FAAH inhibitor that reduces inflammatory pain. Chem Biol 2009, 16(4): 411.[4] Hoshino, Y.; Koide, H.; Urakami, T.; Kanazawa, H.; et al. Recognition, neutralization, and clearance of target peptides in the bloodstream of living mice by molecularly imprinted polymer nanoparticles: A plastic antibody. J Am Chem Soc 2010, 132(19): 6644.[5] Hoshino, Y.; Kodama, T.; Okahata, Y.; Shea, K.J. Peptide imprinted polymer nanoparticles: A plastic antibody. J Am Chem Soc 2008, 130(46): 15242. PHARMA MATTERS | THE CUTTING EDGE OF CHEMISTRY 17
  20. 20. GET THE LATEST CHEMISTRY INSIGHTS Thomson Reuters IntegritySM combines biology, chemistry and pharmacology information to deliver the latest insights into drug discovery and development. From a chemist’s perspective with Integrity you can: • Search based on mechanism of action, structure, or drug name etc. • Understand the drug-target landscape • Create structure-activity relationship tables • link to experimental data and all references • View the latest structures, scaffolds and synthetic routes emerging from conferences, literature and patents • Access “Disease Briefing” reviews on the current status and future trends in drug therapy for specific diseases. Find out more about Integrity: go.thomsonreuters.com/chemistry ABOUT THOMSON REUTERS Thomson Reuters is the leading source of intelligent information for professionals around the world. Our customers are knowledge workers in key sectors of the global economy. We supply them with the intelligent information they need to succeed in fields that are vital to developed and emerging economies such as law, financial services, tax and accounting, healthcare, science and media. Our knowledge and information is essential for drug companies to discover new drugs and get them to market faster, for researchers to find relevant papers and know what’s newly published in their subject, and for businesses to optimize their intellectual property and find competitive intelligence. NOTE TO PRESS: To request further information or permission to reproduce content from this report, please contact: Paul Sandell Phone: + 44 20 7433 4704 Email: paul.sandell@thomsonreuters.com NOT A CURRENT SUBSCRIBER TO THE CUTTING EDGE OF CHEMISTRY? : To sign up for this free Pharma Matters report visit: go.thomsonreuters.com/ceocHEALTHCARE & SCIENCEREGIONAL OFFICESNorth AmericaPhiladelphia +1 800 336 4474 +1 215 386 0100Latin America +55 11 8370 9845Europe, Middle East and AfricaBarcelona +34 93 459 2220London +44 20 7433 4000Asia PacificSingapore +65 6775 5088Tokyo +81 3 5218 6500For a complete office list visit:science.thomsonreuters.com/contactPH1011266Copyright © 2010 Thomson Reuters

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