title: Novel phenylalanine derived diamides as Factor XIa inhibitors.
abstract: The synthesis, structural activity relationships (SAR), and selectivity profile of a potent series of phenylalanine diamide FXIa inhibitors will be discussed. Exploration of P1 prime and P2 prime groups led to the discovery of compounds with high FXIa affinity, good potency in our clotting assay (aPPT), and high selectivity against a panel of relevant serine proteases as exemplified by compound 21. Compound 21 demonstrated good in vivo efficacy (EC50=2.8μM) in the rabbit electrically induced carotid arterial thrombosis model (ECAT).
authors.affiliation: Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, NJ 08543, United States. Electronic address: leon.smith@bms.com.
authors.forename: Leon M
authors.initials: LM
authors.lastname: Smith
authors.affiliation: Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, NJ 08543, United States.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Orwat
authors.affiliation: Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, NJ 08543, United States.
authors.forename: Zilun
authors.initials: Z
authors.lastname: Hu
authors.affiliation: Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, NJ 08543, United States.
authors.forename: Wei
authors.initials: W
authors.lastname: Han
authors.affiliation: Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, NJ 08543, United States.
authors.forename: Cailan
authors.initials: C
authors.lastname: Wang
authors.affiliation: Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, NJ 08543, United States.
authors.forename: Karen A
authors.initials: KA
authors.lastname: Rossi
authors.affiliation: Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, NJ 08543, United States.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Gilligan
authors.affiliation: Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, NJ 08543, United States.
authors.forename: Kumar B
authors.initials: KB
authors.lastname: Pabbisetty
authors.affiliation: Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, NJ 08543, United States.
authors.forename: Honey
authors.initials: H
authors.lastname: Osuna
authors.affiliation: Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, NJ 08543, United States.
authors.forename: James R
authors.initials: JR
authors.lastname: Corte
authors.affiliation: Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, NJ 08543, United States.
authors.forename: Alan R
authors.initials: AR
authors.lastname: Rendina
authors.affiliation: Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, NJ 08543, United States.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Luettgen
authors.affiliation: Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, NJ 08543, United States.
authors.forename: Pancras C
authors.initials: PC
authors.lastname: Wong
authors.affiliation: Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, NJ 08543, United States.
authors.forename: Ranga
authors.initials: R
authors.lastname: Narayanan
authors.affiliation: Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, NJ 08543, United States.
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Harper
authors.affiliation: Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, NJ 08543, United States.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Bozarth
authors.affiliation: Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, NJ 08543, United States.
authors.forename: Earl J
authors.initials: EJ
authors.lastname: Crain
authors.affiliation: Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, NJ 08543, United States.
authors.forename: Anzhi
authors.initials: A
authors.lastname: Wei
authors.affiliation: Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, NJ 08543, United States.
authors.forename: Vidhyashankar
authors.initials: V
authors.lastname: Ramamurthy
authors.affiliation: Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, NJ 08543, United States.
authors.forename: Paul E
authors.initials: PE
authors.lastname: Morin
authors.affiliation: Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, NJ 08543, United States.
authors.forename: Baomin
authors.initials: B
authors.lastname: Xin
authors.affiliation: Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, NJ 08543, United States.
authors.forename: Joanna
authors.initials: J
authors.lastname: Zheng
authors.affiliation: Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, NJ 08543, United States.
authors.forename: Dietmar A
authors.initials: DA
authors.lastname: Seiffert
authors.affiliation: Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, NJ 08543, United States.
authors.forename: Mimi L
authors.initials: ML
authors.lastname: Quan
authors.affiliation: Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, NJ 08543, United States.
authors.forename: Patrick Y S
authors.initials: PYS
authors.lastname: Lam
authors.affiliation: Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, NJ 08543, United States.
authors.forename: Ruth R
authors.initials: RR
authors.lastname: Wexler
authors.affiliation: Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, NJ 08543, United States.
authors.forename: Donald J P
authors.initials: DJP
authors.lastname: Pinto
mesh_terms: D000813:Anilides / Q000138:chemical synthesis / Q000494:pharmacology*; D000818:Animals; D018360:Crystallography, X-Ray; D004285:Dogs; D015945:Factor XIa / Q000037:antagonists & inhibitors*; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D011817:Rabbits; D013329:Structure-Activity Relationship
chemical_list: D000813:Anilides; D010649:Phenylalanine; D015945:Factor XIa
keywords: Anticoagulant; FXIa; Factor XIa; Serine protease; Thrombosis; aPTT