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Bioorg Med Chem. 2016 May 15;24(10):2257-72. doi: 10.1016/j.bmc.2016.03.062. Epub 2016 Apr 1.

Orally bioavailable pyridine and pyrimidine-based Factor XIa inhibitors: Discovery of the methyl N-phenyl carbamate P2 prime group.

Author information

1
Bristol-Myers Squibb Company, Research and Development, P.O. Box 5400, Princeton, NJ 08543, United States. Electronic address: james.corte@bms.com.
2
Bristol-Myers Squibb Company, Research and Development, P.O. Box 5400, Princeton, NJ 08543, United States.

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.

KEYWORDS:

Activated partial thromboplastin time; FXIa; Factor XIa; Thrombosis; aPTT

PMID:
27073051
DOI:
10.1016/j.bmc.2016.03.062
[Indexed for MEDLINE]

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