Design and synthesis of thrombin inhibitors: analogues of MD-805 with reduced stereogenicity and improved potency

…, M McDonnell, GP Smith, R Wakeford…

Index: 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. Journal of Medicinal Chemistry, 1999 , vol. 42, # 22 p. 4584 - 4603

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Citation Number: 29

Abstract

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- ...