title: Orally bioavailable pyridine and pyrimidine-based Factor XIa inhibitors: Discovery of the methyl N-phenyl carbamate P2 prime group.
abstract: Pyridine-based Factor XIa (FXIa) inhibitor (S)-2 was optimized by modifying the P2 prime, P1, and scaffold regions. This work resulted in the discovery of the methyl N-phenyl carbamate P2 prime group which maintained FXIa activity, reduced the number of H-bond donors, and improved the physicochemical properties compared to the amino indazole P2 prime moiety. Compound (S)-17 was identified as a potent and selective FXIa inhibitor that was orally bioavailable. Replacement of the basic cyclohexyl methyl amine P1 in (S)-17 with the neutral p-chlorophenyltetrazole P1 resulted in the discovery of (S)-24 which showed a significant improvement in oral bioavailability compared to the previously reported imidazole (S)-23. Additional improvements in FXIa binding affinity, while maintaining oral bioavailability, was achieved by replacing the pyridine scaffold with either a regioisomeric pyridine or pyrimidine ring system.
authors.affiliation: Bristol-Myers Squibb Company, Research and Development, P.O. Box 5400, Princeton, NJ 08543, United States. Electronic address: james.corte@bms.com.
authors.forename: James R
authors.initials: JR
authors.lastname: Corte
authors.affiliation: Bristol-Myers Squibb Company, Research and Development, P.O. Box 5400, Princeton, NJ 08543, United States.
authors.forename: Tianan
authors.initials: T
authors.lastname: Fang
authors.affiliation: Bristol-Myers Squibb Company, Research and Development, P.O. Box 5400, Princeton, NJ 08543, United States.
authors.forename: Donald J P
authors.initials: DJ
authors.lastname: Pinto
authors.affiliation: Bristol-Myers Squibb Company, Research and Development, P.O. Box 5400, Princeton, NJ 08543, United States.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Orwat
authors.affiliation: Bristol-Myers Squibb Company, Research and Development, P.O. Box 5400, Princeton, NJ 08543, United States.
authors.forename: Alan R
authors.initials: AR
authors.lastname: Rendina
authors.affiliation: Bristol-Myers Squibb Company, Research and Development, P.O. Box 5400, Princeton, NJ 08543, United States.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Luettgen
authors.affiliation: Bristol-Myers Squibb Company, Research and Development, P.O. Box 5400, Princeton, NJ 08543, United States.
authors.forename: Karen A
authors.initials: KA
authors.lastname: Rossi
authors.affiliation: Bristol-Myers Squibb Company, Research and Development, P.O. Box 5400, Princeton, NJ 08543, United States.
authors.forename: Anzhi
authors.initials: A
authors.lastname: Wei
authors.affiliation: Bristol-Myers Squibb Company, Research and Development, P.O. Box 5400, Princeton, NJ 08543, United States.
authors.forename: Vidhyashankar
authors.initials: V
authors.lastname: Ramamurthy
authors.affiliation: Bristol-Myers Squibb Company, Research and Development, P.O. Box 5400, Princeton, NJ 08543, United States.
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Myers
authors.affiliation: Bristol-Myers Squibb Company, Research and Development, P.O. Box 5400, Princeton, NJ 08543, United States.
authors.forename: Steven
authors.initials: S
authors.lastname: Sheriff
authors.affiliation: Bristol-Myers Squibb Company, Research and Development, P.O. Box 5400, Princeton, NJ 08543, United States.
authors.forename: Rangaraj
authors.initials: R
authors.lastname: Narayanan
authors.affiliation: Bristol-Myers Squibb Company, Research and Development, P.O. Box 5400, Princeton, NJ 08543, United States.
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Harper
authors.affiliation: Bristol-Myers Squibb Company, Research and Development, P.O. Box 5400, Princeton, NJ 08543, United States.
authors.forename: Joanna J
authors.initials: JJ
authors.lastname: Zheng
authors.affiliation: Bristol-Myers Squibb Company, Research and Development, P.O. Box 5400, Princeton, NJ 08543, United States.
authors.forename: Yi-Xin
authors.initials: YX
authors.lastname: Li
authors.affiliation: Bristol-Myers Squibb Company, Research and Development, P.O. Box 5400, Princeton, NJ 08543, United States.
authors.forename: Dietmar A
authors.initials: DA
authors.lastname: Seiffert
authors.affiliation: Bristol-Myers Squibb Company, Research and Development, P.O. Box 5400, Princeton, NJ 08543, United States.
authors.forename: Ruth R
authors.initials: RR
authors.lastname: Wexler
authors.affiliation: Bristol-Myers Squibb Company, Research and Development, P.O. Box 5400, Princeton, NJ 08543, United States.
authors.forename: Mimi L
authors.initials: ML
authors.lastname: Quan
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000925:Anticoagulants / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D001777:Blood Coagulation / Q000187:drug effects; D018360:Crystallography, X-Ray; D004285:Dogs; D015945:Factor XIa / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D048448:Phenylcarbamates / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D011725:Pyridines / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D011743:Pyrimidines / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D000925:Anticoagulants; D048448:Phenylcarbamates; D011725:Pyridines; D011743:Pyrimidines; D015945:Factor XIa
keywords: Activated partial thromboplastin time; FXIa; Factor XIa; Thrombosis; aPTT