title: Phenylimidazoles as potent and selective inhibitors of coagulation factor XIa with in vivo antithrombotic activity.
abstract: Novel inhibitors of FXIa containing an (S)-2-phenyl-1-(4-phenyl-1H-imidazol-2-yl)ethanamine core have been optimized to provide compound 16b, a potent, reversible inhibitor of FXIa (Ki = 0.3 nM) having in vivo antithrombotic efficacy in the rabbit AV-shunt thrombosis model (ID50 = 0.6 mg/kg + 1 mg kg(-1) h(-1)). Initial analog selection was informed by molecular modeling using compounds 11a and 11h overlaid onto the X-ray crystal structure of tetrahydroquinoline 3 complexed to FXIa. Further optimization was achieved by specific modifications derived from careful analysis of the X-ray crystal structure of the FXIa/11h complex. Compound 16b was well tolerated and enabled extensive pharmacologic evaluation of the FXIa mechanism up to the ID90 for thrombus inhibition.
authors.affiliation: Research and Development, Bristol-Myers Squibb , P.O. Box 5400, Princeton, New Jersey 08543, United States.
authors.forename: Jon J
authors.initials: JJ
authors.lastname: Hangeland
authors.forename: Todd J
authors.initials: TJ
authors.lastname: Friends
authors.forename: Karen A
authors.initials: KA
authors.lastname: Rossi
authors.forename: Joanne M
authors.initials: JM
authors.lastname: Smallheer
authors.forename: Cailan
authors.initials: C
authors.lastname: Wang
authors.forename: Zhong
authors.initials: Z
authors.lastname: Sun
authors.forename: James R
authors.initials: JR
authors.lastname: Corte
authors.forename: Tianan
authors.initials: T
authors.lastname: Fang
authors.forename: Pancras C
authors.initials: PC
authors.lastname: Wong
authors.forename: Alan R
authors.initials: AR
authors.lastname: Rendina
authors.forename: Frank A
authors.initials: FA
authors.lastname: Barbera
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Bozarth
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Luettgen
authors.forename: Carol A
authors.initials: CA
authors.lastname: Watson
authors.forename: Ge
authors.initials: G
authors.lastname: Zhang
authors.forename: Anzhi
authors.initials: A
authors.lastname: Wei
authors.forename: Vidhyashankar
authors.initials: V
authors.lastname: Ramamurthy
authors.forename: Paul E
authors.initials: PE
authors.lastname: Morin
authors.forename: Gregory S
authors.initials: GS
authors.lastname: Bisacchi
authors.forename: Srinath
authors.initials: S
authors.lastname: Subramaniam
authors.forename: Piramanayagam
authors.initials: P
authors.lastname: Arunachalam
authors.forename: Arvind
authors.initials: A
authors.lastname: Mathur
authors.forename: Dietmar A
authors.initials: DA
authors.lastname: Seiffert
authors.forename: Ruth R
authors.initials: RR
authors.lastname: Wexler
authors.forename: Mimi L
authors.initials: ML
authors.lastname: Quan
mesh_terms: D000818:Animals; D018360:Crystallography, X-Ray; D005343:Fibrinolytic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D007191:Indazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D008958:Models, Molecular; D010314:Partial Thromboplastin Time; D011817:Rabbits; D013927:Thrombosis / Q000517:prevention & control
chemical_list: D005343:Fibrinolytic Agents; D007093:Imidazoles; D007191:Indazoles; C000595392:trans-N-((S)-1-(4-(3-amino-1H-indazol-6-yl)-5-chloro-1H-imidazol-2-yl)-2-phenylethyl)-4-(aminomethyl)cyclohexanecarboxamide