Design and synthesis of a series of potent and orally bioavailable noncovalent thrombin inhibitors that utilize nonbasic groups in the P1 position.
As part of an ongoing effort to prepare therapeutically useful orally active thrombin inhibitors, we have synthesized a series of compounds that utilize nonbasic groups in the P1 position. The work is based on our previously reported lead structure, compound 1, which was discovered via a resin-based approach to varying P1. By minimizing the size and lipophilicity of the P3 group and by incorporating hydrogen-bonding groups on the N-terminus or on the 2-position of the P1 aromatic ring, we have prepared a number of derivatives in this series that exhibit subnanomolar enzyme potency combined with good in vivo antithrombotic and bioavailability profiles. The oxyacetic amide compound 14b exhibited the best overall profile of in vitro and in vivo activity, and crystallographic studies indicate a unique mode of binding in the thrombin active site.
Departments of Medicinal Chemistry, Biological Chemistry, Pharmacology, Drug Metabolism, and Molecular Design and Diversity, Merck Research Laboratories, West Point, Pennsylvania 19486, USA.
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TJ
Tucker
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Brady
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Lumma
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Lewis
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Gardell
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Naylor-Olsen
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Yan
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Sisko
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KJ
Stauffer
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BJ
Lucas
J J
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Lynch
J J
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Cook
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Stranieri
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Holahan
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Lyle
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Baskin
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Chen
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Dancheck
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Krueger
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Cooper
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Vacca
D000284:Administration, Oral; D000818:Animals; D001665:Binding Sites; D001682:Biological Availability; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D003514:Cyclohexylamines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D004151:Dipeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D004285:Dogs; D015195:Drug Design; D005343:Fibrinolytic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D006860:Hydrogen Bonding; D008252:Macaca fascicularis; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D051381:Rats; D012116:Resins, Plant; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000037:antagonists & inhibitors* / Q000737:chemistry
D003514:Cyclohexylamines; D004151:Dipeptides; D005343:Fibrinolytic Agents; D012116:Resins, Plant; D013917:Thrombin