The Cutting Edge of Chemistry, Jan. - Mar. 2010 -- Pharma Matters Report
Image CopyrIght: REUTERS/Bogdan CristelTHE CUTTING EDGEOF CHEMISTRYA PHARMA MATTERS REPORT.JANUARY - MARCH 2010 NEW! Action-packed chemistry review providing insight into the latest synthesis schemes, scaffolds, mechanisms of actions and new structures advancing drug discovery and development.
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 new 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. The Organic Synthesis Scheme Showcase presents a selection of cutting- edge organic syntheses for drugs currently on the market or in development worldwide and described in premier publications in medicinal chemistry as well as in the current patent literature. This section provides access to the state-of- the-art synthetic methods for bioactive compounds, as well as demonstrating how new synthetic methods lead to interesting intermediates or drugs. Chemists often start with a novel chemical structure in the drug discovery process. Molecular scaffolds are the building blocks with which they build more sophisticated active compounds. Chemists have so far explored only small regions of the vast molecular universe looking for therapeutic agents, but are constantly pushing back the frontiers. Scaffolds on the Move relates efforts in this arena. Finding new targets to address more selectively is crucial to sustaining a competitive advantage in pharmaceutical research. Indeed, accurate target identification and validation processes in the very early stages of any drug R&D project can make the difference between success and failure in the clinical application of a new drug as well as a strong intellectual property strategy. The New Molecular Mechanisms of Action feature highlights this critical aspect of early-stage research. The Starting Line includes a series of new molecular entities just entering the R&D pipeline. Novel, biologically active molecules picked from the current scientific literature and meetings are revealed in this section. Not surprisingly, these research projects from industry and academia are the culmination of the earlier steps in the process: discovery of an original chemical structure, identification of an appealing new mechanism of action, and determination of synthetic feasibility. Thomson Reuters has widely applied in the design of its products and services the dynamics driving end-user information needs. The Cutting Edge of Chemistry is the most recent addition to this concept and we expect it will constitute, together with the existing Pharma Matters reports, a useful addition to your reading list. IN THIS ISSUE 1 orgaNIC SyNtheSIS SCheme ShoWCaSe Marine natural products prove useful as leads repeatedly. A novel synthetic approach to a rare peptide from a marine sponge opens the door for evaluating its promising biological activity. 4 SCaFFoLDS oN the moVe A wide range of new skeletons emphasize the point that novel chemical scaffolds with biological activity underpin major advances in medicinal chemistry. 7 NeW moLeCULar meChaNISmS oF aCtIoN Mechanisms are key to finding ways to improve a given drug design and also to find still more potent leads with fewer potential side effects. 9 the StartINg LINe & target FoCUS Highlighted in this issue, the rise of new molecular entities in the cancer and CNS R&D arenas.PHARMA MATTERS | THE CUTTING EDGE OF CHEMISTRY A
ORGANIC SYNTHESIS SCHEMESHOWCASE: SoakINg uppolyTheoNaMIDe B SyNTheSISpolytheonamides a and B (pa and pB) were first isolated fromthe coral reef sponge Theonella swinhoei, a well-known source ofnovel natural products with physiological activity. What makespB particularly interesting is that it can stimulate an ion fluxacross cell membranes and quickly kill cells. The compound hasbeen investigated for a potential role in treating leukemia as it iscytotoxic against a strain of mouse leukemia p388 cells.Researchers have assumed that a symbiotic microorganismpresent in T. swinhoei is responsible for the biosynthesis of pB.as such, the total synthesis of pB has represented a challenge.Masayuki Inoue of the graduate School of pharmaceuticalSciences, The university of Tokyo, and colleagues have nowobtained good yields in a laboratory synthesis involving acoupling reaction between appropriate segments of pB usingthioligation with silver ions .In detail, the team uses a four-stage synthesis. The firststep is the synthesis of the required amino acids, which arenot commonly found in proteins. The second stage is thepreparation of the required peptide fragments by solid-phaseassembly of the protected amino acids over a Wang resin. afterderivatization of the three fragments into thioesters, they areinter-connected, in the third stage, by means of silver ions inprocesses with yields of about 85%. The fourth and final stepinvolves global deprotection.The researchers add that the stereoselective synthesis of thesulfoxide from the sulfide precursor and its stereochemicalassignment were not simple tasks, primarily because chiralreagents for sulfide oxidation do not exhibit diastereoselectivity.however, by turning to katsuki conditions the team was able topromote a highly diastereoselective oxidation to the final product.This invaluable approach to peptide disconnections andprotecting-group strategy not only has made it much morestraightforward to synthesize such a significant compound aspB, but could allow chemists to construct other polypeptidedrugs for testing against a range of disorders. Inoue andcolleagues also point out, “The synthetic material now availablewill allow studies of the relationships between its conformationalproperties, channel functions and cytotoxicity.”Indeed, Inoue and colleagues conclude, “This attempt to gainprecise atom-by-atom control of the structure will provide thefirst chemical basis for systematically correlating its molecularstructure and biological function.”INTEGRITY ENTRY NUMBER: 691631 PHARMA MATTERS | THE CUTTING EDGE OF CHEMISTRY 1
Synthesis scheme for Polytheonamide B (Part 1) O O O O O O H H H H H N N N Ile N N E tO S L T le Fmoc H H N N H 3C C H3 HO C H3 C H3 OH O O (I) HOOBt, AgNO 3 , DIEA N N O O O O O H H H H H N N N N Ile N N O L T le Fmoc H H O N N H 3C C H3 HO C H3 C H3 OH O O O (II) Ile NH 2 H N C H3 O O T rt O O O O N H H H H HN Val N Ala N Val D Ser N N O H H H N C H3 H N N C H3 H 3C C H3 O t BuO C H3 + C H3 NH S O O O O O HO Thr(tBu) D Thr(tBu) G ln(T rt) NH H 3 C C H 3 O Pip NH T rt (III) O O O O H H H H Ile N G ly N N Ile N G ly NH 2 L T le H H H N N N C H 3 H 3C C H3 HO C H3 C H3 O OH O O O T rt O O O O N H H H H HN Val N Ala N Val D Ser N O N H H H N C H3 H N N C H3 H 3C C H3 O t BuO C H3 + C H3 NH S O O O O O HO Thr(tBu) D Thr(tBu) G ln(T rt) NH H 3 C C H 3 O C H3 H 3C C H3 NH T rt L Tle OH H 2N (IV) Synthesis scheme for Polytheonamide B (Part 2) O O O O O continued H H H H Ile N G ly N N Ile N G ly NH 2 L T le H H H N N N C H 3 H 3C C H3 HO C H3 C H3 O OH O O O T rt O O O O N H H H H continues HN Val N Ala N Val D Ser N O N H H H N C H3 H N N C H3 H 3C C H3 O t BuO C H3 + C H3 NH S O O O O OH O H 3C C H3 O C H3 O HO Thr(tBu) D Thr(tBu) G ln(T rt) NH H C H H 3 O N Ala D T le N N Fmoc O H O C H3 O NH 2 NH HN T rt C H3 H 3C O O O H H H N N G ly Ala G ly L T le N Ala G ly S OE t (IV) H H O N H 3C C H3 C H3 OH O (V) 1) HOOBt, AgNO3 , DIEA 2) Pip OH H 3C C H3 O H O N Ala D T le Ala NH 2 N H O O NH 2 HN C H3 H 3C O O H H H N N Ala G ly Ala G ly L T le N H H O N H 3C C H3 C H3 OH G ly O O O O O H H H H Ile N G ly N N Ile N G ly L T le H H H N N N C H 3 H 3C C H3 HO C H3 C H3 O OH O O O T rt O O O O N H H H H O HN Val N Ala N Val D Ser N N H H H N C H3 H N N C H3 H 3C C H3 O C H3 t BuO C H3 + NH S O O O O O HO Thr(tBu) D Thr(tBu) G ln(T rt) NH H 3 C C H 3 O C H3 NH H 3C C H3 T rt D Tle OH (VI) continues H 2N O2 PHARMA MATTERS | THE CUTTING EDGE OF CHEMISTRY
Synthesis scheme for Polytheonamide B (Part 3) continued OH H 3C C H3 O HO N Ala D T le Ala NH 2 N H O O NH 2 HN C H3 H 3C O O C H3 O O H H H H 3C H N N Ala G ly N G ly L T le D T le L T le D Ala G ly Ala G ly L T le N H 3C H O O H H 3C C H3 CH N CH 3 L T le C H3 OH G ly C H3 3 O E tO S G ly Ala D T le O O O O H H H H O Ile N G ly N N Ile N G ly L T le H H H (VII) N N N C H 3 H 3C C H3 HO C H3 C H3 O OH O O O T rt O O O O N H H H H O HN Val N Ala N Val D Ser N N H H H N C H3 H N N C H3 H 3C C H3 O C H3 t BuO C H3 + NH S O O O O O 1) HOOBt, AgNO 3, DIEA NH H 3 C C H3 2) TFA HO Thr(tBu) D Thr(tBu) G ln(T rt) O NH T rt (VI) C H3 O O H 3C H G ly N G ly L T le D T le L T le D Ala H 3C O C H3 C H3 C H3 L T le OH H 3C C H3 O H O N Ala D T le Ala G ly Ala D T le N H O O NH 2 HN H 3C C H3 O O H H H N N Ala G ly Ala G ly L T le N H H O N H 3C C H3 G ly C H3 OH O O O O O H H H H Ile N G ly N N Ile N G ly L T le H H H N N N C H 3 H 3C C H3 HO C H3 C H3 OH O O O O O O H H HN Val N Ala N Val D Ser Val D Asn H H H N N N C H3 HO C H3 C H3 O O O O C OOH Thr D Thr G ln D Asn NH O H 3C S + C H3 H 3CDiastereoselective oxidation of sulfide to sulfoxide (Katsuki conditions) H 3C H 3C + O S S C H3 1) H 2NCONH 2.H 2O 2, C H3 C H3 di-µ-oxo Ti(salen) C H3 Fmoc O Fmoc OH N t-Bu N H 2) TFA H O O PHARMA MATTERS | THE CUTTING EDGE OF CHEMISTRY 3
SCAFFOLDS ON THE MOVE Novel chemical scaffolds with biological activity underpin major advances in medicinal chemistry. In this issue, a wide range of new skeletons emphasize this point once again. For instance, a series of 2-arylbenzoxazoles from Merck & Co. offers hope in treating lipid disorders and atherosclerosis, while arthritis is the target of almirall’s new dihydroorotate dehydrogenase inhibitors. a promising skeleton, carene, from Novartis also features in this issue and offers a new lead for treating transplant rejection. BENZOXAZOLE BLOCKS CHOLESTEROL TRANSFER Merck scientists have developed a series of 2-arylbenzoxazoles that block cholesteryl ester transfer protein (CeTp) and so might be useful in treating lipoprotein disorders and disorders of the coronary arteries as well as atherosclerosis. Their structure-activity studies on the impact of varying the substitution of the benzoxazole moiety suggest that substitution at the 5- and 7-positions is beneficial to CeTp inhibition. The most potent compound of the series has an IC50 of 28 nM. NC N THERAPEUTIC GROUP: SOURCE: O C H3 Treatment of lipoprotein Disorders; Smith, C.J.; ali, a.; Chen, l.; O C H3 O Treatment of Coronary arteries and hammond, M.l.; et al. N HO H atherosclerosis Disorders 2-arylbenzoxazoles as CeTp C H3 STUDIED MECHANISM OF ACTION: inhibitors: Substitution of the Cholesteryl ester Transfer protein benzoxazole moiety. (CeTp) Inhibitors Bioorg Med Chem Lett 2010, 20(1): 346. ORGANIZATION: INTEGRITY ENTRY NUMBER: Merck & Co. 684173 O OH ANTI-INFLAMMATORY AMINO(ISO)NICOTINIC ACIDS F H arthritis is the focus of novel, patented dihydroorotate dehydrogenase N (DhoDh) inhibitors from almirall, that are orally active and could be suitable N O F for treating autoimmune conditions, such as rheumatoid arthritis. The potent F F amino(iso)nicotinic acid derivatives represent a new scaffold for DhoDh C H3 F inhibitors, one biaryl derivative showing an IC50 of 6 nM against human DhoDh (featured molecule). Structure-activity studies and optimization of the series led to one particular compound (chemical structure undisclosed) with potent in vitro activity against human, rat and mouse DhoDh (IC50 values of 0.037, 0.034 and 0.07 µM, respectively) compared with that of teriflunomide (respective IC50 values of 1.5, 0.033 and 1.1 µM). The compound also inhibits proliferation of human peripheral blood mononuclear cells more effectively and has demonstrated efficacy in reducing inflammation, as measured by paw volume, in a rat model. THERAPEUTIC GROUP: SOURCE: antiarthritic Drugs erra, M.; Sanahuja, J.; Fonquerna, STUDIED MECHANISM OF ACTION: S.; Navarro, e.; et al. Dihydroorotate Dehydrogenase Best in class DhoDh inhibitors: (DhoDh) Inhibitors evolution of clinical compounds. 239th aCS Natl Meet (March 21-25, San Francisco) 2010, abst MeDI 461. ORGANIZATION: almirall INTEGRITY ENTRY NUMBER: 6912514 PHARMA MATTERS | THE CUTTING EDGE OF CHEMISTRY
IMIDAZO[1,2-a] PYRAZINE ANTICANCER DRUGS Haurora-a (aRk1) kinase and aurora-B (aRk2) kinase are two enzymes N Nover-expressed in tumors. Belonging to a family of three Ser/Thr kinases,they are critical regulators of mitosis, abundant in tumors, and so have H 3Cbeen longstanding targets for anticancer compounds. Merck has recently Ndisclosed novel dual inhibitors of aurora kinases a and B based on an N N H 3C C H3imidazo[1,2-a] pyrazine scaffold. lead optimization allowed for the HN OHidentification of progression candidates, albeit they showed poor oral Nbioavailability. The sites of metabolism were identified by studying the S Nmetabolic profile of a particular compound of the series. C H3THERAPEUTIC GROUP: SOURCE:oncolytic Drugs kerekes, a.D.; esposite, S.J.; Doll,STUDIED MECHANISM OF ACTION: R.J.; yu, T.; et al.aurora-a (aRk1) kinase Inhibitors; aurora kinase inhibitors basedaurora-B (aRk2) kinase Inhibitors on the imidazolopyrazine core: Fluorine incorporation improves oral absorption and exposure. 239th aCS Natl Meet (March 21-25, San Francisco) 2010, abst MeDI 146. yu, T.; Tagat, J.R.; Zhang, y.; Xiao, y.; et al. Discovery of aurora kinase inhibitors based on 3,6,8-trisubstituted imidazo[1,2-a] pyrazine scaffold. 239th aCS Nat Meet (March 21-25, San Francisco) 2010, abst MeDI 145.ORGANIZATION: INTEGRITY ENTRY NUMBER:Merck & Co. 689948PYRAZOLES AVOID REJECTION H 3C C H3employing a high-throughput screening and hit-to-lead optimization H 3Capproach, Novartis has come out with a new carene scaffold displaying Nselective S1p1 agonist properties. Furthermore, the key structural requisites Nfor potent agonism were also outlined by building up a pharmacophore NHmodel for the S1p1 receptor, a biological target for immunosuppression Oand the treatment of transplant rejection.THERAPEUTIC GROUP: SOURCE:Immunosuppressants; Treatment of Zécri, F.J.; albert, R.; landrum, g.;Transplant Rejection hinterding, k.; et al.STUDIED MECHANISM OF ACTION: pyrazole derived from (+)-3-carene;lysophospholipid edg1 (S1p1) a novel potent, selective scaffoldReceptor agonists for sphingosine-1-phosphate (S1p1) receptor agonists. Bioorg Med Chem Lett 2010, 20(1): 35. Zécri, F.J.; albert, R.; Baenteli, R.; landrum, g.; et al. Discovery and optimization of multiple scaffolds of selective S1p1 receptor agonists. 239th aCS Natl Meet (March 21-25, San Francisco) 2010, abst MeDI 31.ORGANIZATION: INTEGRITY ENTRY NUMBER:Novartis 369046 PHARMA MATTERS | THE CUTTING EDGE OF CHEMISTRY 5