Design and Synthesis of Thrombin Inhibitors: Analogues of MD-805 with Reduced Stereogenicity and Improved Potency

Mitsubishi's MD-805, a potent and selective inhibitor of thrombin which contains four stereogenic centers, has been the starting point for an optimization program. A systematic synthetic study resulted in thrombin inhibitors achiral at P2 and P3 but with a 10-fold increase in potency over the o...

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Bibliographic Details
Published in:	Journal of medicinal chemistry Vol. 42; no. 22; pp. 4584 - 4603
Main Authors:	Brundish, Derek, Bull, Alice, Donovan, Vera, Fullerton, Joseph D, Garman, Sheila M, Hayler, Judy F, Janus, Diana, Kane, Peter D, McDonnell, Mark, Smith, Garrick P, Wakeford, Robert, Walker, Clive V, Howarth, Graham, Hoyle, William, Allen, Mark C, Ambler, John, Butler, Keith, Talbot, Mark D
Format:	Journal Article
Language:	English
Published:	Washington, DC American Chemical Society 04-11-1999
Subjects:	Animals Antithrombins - administration & dosage Antithrombins - chemical synthesis Antithrombins - chemistry Antithrombins - pharmacology Biological and medical sciences Blood. Blood coagulation. Reticuloendothelial system Cattle Drug Design Humans Injections, Intravenous Injections, Subcutaneous Medical sciences Models, Molecular Pharmacology. Drug treatments Pipecolic Acids - chemistry Pipecolic Acids - pharmacology Piperidines - administration & dosage Piperidines - chemical synthesis Piperidines - chemistry Piperidines - pharmacology Rats Stereoisomerism Structure-Activity Relationship Thrombin - antagonists & inhibitors Thrombosis - drug therapy Intravenous administration Rat Nitrogen heterocycle Cardiovascular disease Non peptide compound Thrombin Anticoagulant Vascular disease Structure activity relation Piperidine derivatives Subcutaneous administration Chemical synthesis Sulfonamide Serine endopeptidases Enzyme Rodentia Enzyme inhibitor Quinoline derivatives Guanidines In vitro Thrombosis Primary alcohol Peptidases In vivo α-Aminoacid Vertebrata Chemotherapy Experimental disease Mammalia Treatment Animal Hydrolases Carboxamide
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Summary:	Mitsubishi's MD-805, a potent and selective inhibitor of thrombin which contains four stereogenic centers, has been the starting point for an optimization program. A systematic synthetic study resulted in thrombin inhibitors achiral at P2 and P3 but with a 10-fold increase in potency over the original lead. A number of 4-substituted piperidines were synthesized and examined as replacements for 2-carboxy-4-methylpiperidine at P2; 4-fluoroethylpiperidine (FEP) among others provided inhibitors (e.g. 45g) of increased potency. An enantioselective route was developed to 3(R)-methyl-1,2,3,4-tetrahydroquinolinesulfonyl chloride. Inhibitors containing this enantiomerically pure P3 (42d) had similar potency to the racemic material and provided support, with modeling studies, for the preparation of the gem 3,3-disubstituted compounds. A series of inhibitors containing the novel 3,3-dimethyl-1,2,3,4-tetrahydroquinolinesulfonyl (DMTHQS) P3 (Table ) were synthesized and showed a similar activity profile as the monomethyl series. The combination of P3-DMTHQS, P2-FEP, and P1-arginine (45 g ) had a K i of 6 nM (MD-805 K i = 85 nM). In animal models of both venous and arterial thrombosis, one inhibitor (42e) was shown to produce a dose-dependent inhibition of thrombus formation that in some situations was superior to that of MD-805.
Bibliography:	istex:A6930FDF6C51BC0776FB22A0F18C924B8F871531 ark:/67375/TPS-1FS9TP2M-T ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0022-2623 1520-4804
DOI:	10.1021/jm9811209