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.

Recent advances in the discovery and development of factor XI/XIa inhibitors

“…These groups included 1-aminobenzoic acid-4-yl, benzoic acid-3-yl, aniline-4-yl, 2-aminopyridine-5-yl, and methylcarbamate-4-yl. The most potent analog in this series was (S)-inhibitor 70 (Figure 16) that has a K i value of 6.3 nM and APTT EC 1.5x of 2.6 M. Replacement of the pyridine group in this inhibitor with pyridinone led to inhibitor 71 (Figure 16), which has a K i value of 2.4 nM and APTT EC 1.5x of 0.4 M. 133 Another set of molecules studied in the same report was that in which the basic cyclohexyl methyl amine P1 was replaced with a neutral para-chlorophenyltetrazole P1 in the regioisomeric pyridine, pyrimidine, and pyridinone analogs. The regioisomeric pyridine 73, pyrimidine 74, and pyridinone 75 ( Figure 17) possessed improved FXIa binding activity and potency in the clotting assay compared to pyridine 72 (Figure 17).…”

“…The most potent analog in this series was ( S )‐inhibitor 70 (Figure ) that has a K i value of 6.3 nM and APTT EC 1.5 x of 2.6 μM. Replacement of the pyridine group in this inhibitor with pyridinone led to inhibitor 71 (Figure ), which has a K i value of 2.4 nM and APTT EC 1.5 x of 0.4 μM …”

“…The same research group reported further optimization of inhibitor 53 . The aminoindazole group of S2ʹ pocket was replaced with an unsubstituted indazole, 3‐hydroxyindazole, 3‐aminobenzisoxazole, 4‐amino‐quinazoline, and 1‐aminoisoquinoline.…”

“…The tetrazole moiety interacts with the Cys191–Cys219 disulfide bridge. Moreover, the tetrazole N 4 nitrogen forms a water‐mediated H‐bond with the Gly218 residue …”

“…Lastly, as with the previously published FXIa inhibitors, select inhibitors from this series were tested against other serine proteases including FVIIa, FIXa, FXa, thrombin, APC, plasmin, chymotrypsin, urokinase, and tPA and were found to be significantly selective. Yet, they were found to moderately inhibit trypsin (selectivity index of ninefold to 270‐fold) and plasma kallikrein (selectivity index of threefold to 150‐fold) …”