title: Design and synthesis of thrombin inhibitors: analogues of MD-805 with reduced stereogenicity and improved potency.
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-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 5) were synthesized and showed a similar activity profile as the monomethyl series. The combination of P3-DMTHQS, P2-FEP, and P1-arginine (45g) 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.
authors.affiliation: Department of Chemistry, Drug Discovery Support, Novartis Horsham Research Centre, Wimblehurst Road, Horsham, West Sussex RH12 5AB, U.K.
authors.forename: D
authors.initials: D
authors.lastname: Brundish
authors.forename: A
authors.initials: A
authors.lastname: Bull
authors.forename: V
authors.initials: V
authors.lastname: Donovan
authors.forename: J D
authors.initials: JD
authors.lastname: Fullerton
authors.forename: S M
authors.initials: SM
authors.lastname: Garman
authors.forename: J F
authors.initials: JF
authors.lastname: Hayler
authors.forename: D
authors.initials: D
authors.lastname: Janus
authors.forename: P D
authors.initials: PD
authors.lastname: Kane
authors.forename: M
authors.initials: M
authors.lastname: McDonnell
authors.forename: G P
authors.initials: GP
authors.lastname: Smith
authors.forename: R
authors.initials: R
authors.lastname: Wakeford
authors.forename: C V
authors.initials: CV
authors.lastname: Walker
authors.forename: G
authors.initials: G
authors.lastname: Howarth
authors.forename: W
authors.initials: W
authors.lastname: Hoyle
authors.forename: M C
authors.initials: MC
authors.lastname: Allen
authors.forename: J
authors.initials: J
authors.lastname: Ambler
authors.forename: K
authors.initials: K
authors.lastname: Butler
authors.forename: M D
authors.initials: MD
authors.lastname: Talbot
mesh_terms: D000818:Animals; D000991:Antithrombins / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001120:Arginine / Q000031:analogs & derivatives; D002417:Cattle; D015195:Drug Design; D006801:Humans; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D008958:Models, Molecular; D010875:Pipecolic Acids / Q000737:chemistry* / Q000494:pharmacology; D010880:Piperidines / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013449:Sulfonamides; D013917:Thrombin / Q000037:antagonists & inhibitors*; D013927:Thrombosis / Q000188:drug therapy
chemical_list: D000991:Antithrombins; D010875:Pipecolic Acids; D010880:Piperidines; D013449:Sulfonamides; D001120:Arginine; D013917:Thrombin; C031942:argatroban