![Portoghese, P.S., S. Ohkawa, and S.T. Moe. Preparation of spiroindane opiate analogs; 1994. U. S. Pat. 5,298,622
Kshirsagar, T.A., S.T. Moe, and P.S. Portoghese. Stereospecific synthesis of pseudocodeine: [2,3]-Sigmatropic rearrangement using selenium intermediates. J. Org. Chem. 63(5), 1704-1705, 1998.
Portoghese, P.S., S. Ohkawa, S.T. Moe, and A.E. Takemori. Synthesis and delta-opioid receptor antagonist activity of naltrindole analogues with a regioisomeric indole moiety. J. Med. Chem. 37(12), 1886-1888, 1994.
Portoghese, P.S., M. Sultana, S.T. Moe, and A.E. Takemori. Synthesis of naltrexone-derived δ-opioid antagonists. Role of conformation of the δ address moiety. J. Med. Chem. 37(5), 579-585, 1994.
Portoghese, P.S., S.T. Moe, and A.E. Takemori. A selective delta-1 opioid receptor agonist derived from oxymorphone. Evidence for separate recognition sites for delta-1 opioid receptor agonists and antagonists. J. Med. Chem. 36(17), 2572-2574, 1993.
Kong, H., K. Raynor, K. Yasuda, S.T. Moe, P.S. Portoghese, G.I. Bell, and T. Reisine. A single residue, aspartic acid 95, in the δ-opioid receptor specifies selective high-affinity agonist binding. J. Biol. Chem. 268(31), 23055-23058, 1993.
morphine
enkephalin
Opioid Antagonists](data:image/gif;base64,R0lGODlhAQABAIAAAAAAAP///yH5BAEAAAAALAAAAAABAAEAAAIBRAA7)
Recommended
Recommended
More Related Content
What's hot
What's hot (20)
Viewers also liked
Viewers also liked (11)
Similar to S.T. Moe publications on opioid receptor ligands
Similar to S.T. Moe publications on opioid receptor ligands (20)
Recently uploaded
Recently uploaded (20)
S.T. Moe publications on opioid receptor ligands
- 1. Cannon, J.G., S.T. Moe, J.P. Long, and R.K. Bhatnagar. S-11-hydroxy-10-methylaporphine and its biologically active salt forms as 5HT1A inhibitors; 1993. U.S. Pat. 5,258,384. Cannon, J.G., R. Raghupathi, and S.T. Moe. Preparation and pharmacological evaluation of enantiomers of certain nonoxygenated aporphines: (+)- and (-)-aporphine and (+)- and (-)-10-methylaporphine. J. Med. Chem. 36(10) 1316-1318, 1993. Cannon, J.G., S.T. Moe, and J.P. Long. Enantiomers of 11-hydroxy-10-methylaporphine having opposing pharmacological effects at 5-HT1A receptors. Chirality 3(1), 19-23, 1991. Dopamine versus serotonin Antagonist versus agonist dopamine serotonin SM-1000 (serotonin inhibitor) Serotonin & Dopamine
- 2. Portoghese, P.S., S. Ohkawa, and S.T. Moe. Preparation of spiroindane opiate analogs; 1994. U. S. Pat. 5,298,622 Kshirsagar, T.A., S.T. Moe, and P.S. Portoghese. Stereospecific synthesis of pseudocodeine: [2,3]-Sigmatropic rearrangement using selenium intermediates. J. Org. Chem. 63(5), 1704-1705, 1998. Portoghese, P.S., S. Ohkawa, S.T. Moe, and A.E. Takemori. Synthesis and delta-opioid receptor antagonist activity of naltrindole analogues with a regioisomeric indole moiety. J. Med. Chem. 37(12), 1886-1888, 1994. Portoghese, P.S., M. Sultana, S.T. Moe, and A.E. Takemori. Synthesis of naltrexone-derived δ-opioid antagonists. Role of conformation of the δ address moiety. J. Med. Chem. 37(5), 579-585, 1994. Portoghese, P.S., S.T. Moe, and A.E. Takemori. A selective delta-1 opioid receptor agonist derived from oxymorphone. Evidence for separate recognition sites for delta-1 opioid receptor agonists and antagonists. J. Med. Chem. 36(17), 2572-2574, 1993. Kong, H., K. Raynor, K. Yasuda, S.T. Moe, P.S. Portoghese, G.I. Bell, and T. Reisine. A single residue, aspartic acid 95, in the δ-opioid receptor specifies selective high-affinity agonist binding. J. Biol. Chem. 268(31), 23055-23058, 1993. morphine enkephalin Opioid Antagonists
- 3. SensiparSensipar®® (Cinacalcet)(Cinacalcet) • Sensipar (Cinacalcet)Sensipar (Cinacalcet) • NPS1506 (Delucemine)NPS1506 (Delucemine) • Ronacaleret (Glaxo)Ronacaleret (Glaxo) • NPS1776 (Abbott)NPS1776 (Abbott) 50 uM lead The Merck Index, 14th Edition (online) Monograph number: 02282 Antihyperparathyroid drug Hyperparathyroidism
- 4. Factors Influencing Pharmaceutical Product Design Natural Product Drug Models (Phytomedicinals) Absorption, Distribution, Metabolism, Excretion Safety, Toxicology Neurotransmitter-Like Compounds Pharmaceutical Perspective, (“Drug-like” Scaffolds) Soft Drug Approach Weak Drug Approach Commercially Successful Drug Products, (Templates) Pharmaceutical Relevance (Marketability) ?Pharmacology Synthetic Accessibility Drug Design
- 5. • Lidocaine synthesisLidocaine synthesis • USP Purity/UV AnalysisUSP Purity/UV Analysis • OctaethylporphoryrinOctaethylporphoryrin • 7-step synthesis7-step synthesis • Natural product purificationNatural product purification • Botonical identificationBotonical identification • IbuprophenIbuprophen • Qualitative identificationQualitative identification Local Anesthetics and Pain
- 6. Step 1: Finding a ring system NMDA antagonism (IC50) in rat cerebellar granular cells (RCGCs) NH2 O (2600 nM) NH2 S (676 nM) NH2 (69 nM) NH2 O (1780 nM) NH2 (1500 nM) N NH2 (609 nM) NMDA Inhibitors
- 7. Drug Discovery CycleDrug Discovery Cycle DATA MINING Drug Discovery Cycle ANALOG DESIGN
- 8. Design of Conformationally Restricted Analogs NH2 F F NH2 F F NH2 F F NH2 F F NH2 F F X-Ray Crystal Analysis from: S.T. Moe, J. Clardy, et al., Bioorg. Med. Chem. Lett. 1999, 9, 1915-1920. Structural Rigidification
- 9. 1506 reduces infarct volume by approximately 50% in animal models of stroke NPS 1506 - Novel NMDA Antagonist Control NPS 1506 Ischemic Stroke
- 10. 2000 Parke-Davis/Pfizer2000 Parke-Davis/Pfizer • Medicinal ChemistryMedicinal Chemistry • Physical-ChemicalPhysical-Chemical PropertiesProperties • ADMEADME • LeadershipLeadership • TeamworkTeamwork Drug-Like Property Analysis
- 11. 300x Antibacterial Potency300x Antibacterial Potency • D-Ala-D-Ala LigaseD-Ala-D-Ala Ligase • Cell wall synthesisCell wall synthesis • Structure-based DesignStructure-based Design • Parallel SynthesisParallel Synthesis • 5-Approach Strategy5-Approach Strategy 30 uM 0.1 uM D-Ala Ligase Inhibitors
- 12. Complementary Approaches to Analog Design Active-site Residue Targeting (Crystallography). Identify residues within reach of ligand and design analogs with complementary functional groups within range of residue Virtual-Library Docking (Modeling). Dock virtual library molecules into active-site models and score. SAR-Driven Substituent Selection (Biochemistry). Use biochemical data as a guide to select “active” functional groups. Traditional, Systematic Analoging (Synthetic Chemistry). Directed at specific questions, e.g., polarity, electronic effects, logP Diversity Analysis (Computational Chemistry). Select a diverse set of functional groups to explore chemical space, Drug Design Strategies
- 13. Parallel Synthesis • Analogs selected using the 5-approaches • 80 analogs per week • Solution phase • 5-chemists in-house • 6-step synthesis • R3-Variation on step 1 !!! D-Ala Ligase Crystal Structures
- 15. Michaelis Complex Model FXIa • Michaelis complex (green) moved from the acylated structure (grey) but the primary interactions remain intact • Phenylurea in the prime sites (left) • Guanidino in the S1 pocket (center) • Acid still H-binding to the waters • Lactam C=O close to Oγ-Ser195 and pointing toward the “oxyanion hole” Factor XIa Crystal Structure
- 16. Silvaggi N.R., et al., Chem. Biol. 14(5):533-42, 2007. 600 analogs via Solid phase synthesis Moe, S.T., et al., Bioorg. Med. Chem. (manuscript submitted Jan. 2009). Botulism Antitoxins
Editor's Notes
- Outline of strategy was use when presented with the dilemma of what to synthesize. Strategy is to use 5 complementary approaches, simultaneously. Read slide. Note: we are currently evaluating whether divesity analysis or similarity analysis would be more suitable.