Download MendeleyOrally bioavailable amine-linked macrocyclic inhibitors of factor XIa.
Fang, T., Corte, J.R., Gilligan, P.J., Jeon, Y., Osuna, H., Rossi, K.A., Myers Jr., J.E., Sheriff, S., Lou, Z., Zheng, J.J., Harper, T.W., Bozarth, J.M., Wu, Y., Luettgen, J.M., Seiffert, D.A., Wexler, R.R., Lam, P.Y.S.(2020) Bioorg Med Chem Lett 30: 126949-126949
- PubMed: 31932224
- DOI: https://doi.org/10.1016/j.bmcl.2020.126949
- Primary Citation of Related Structures:
5QTV, 5QTW, 5QTX, 5QTY - PubMed Abstract:
The discovery of orally bioavailable FXIa inhibitors has been a challenge. Herein, we describe our efforts to address this challenge by optimization of our imidazole-based macrocyclic series. Our optimization strategy focused on modifications to the P2 prime, macrocyclic amide linker, and the imidazole scaffold. Replacing the amide of the macrocyclic linker with amide isosteres led to the discovery of substituted amine linkers which not only maintained FXIa binding affinity but also improved oral exposure in rats. Combining the optimized macrocyclic amine linker with a pyridine scaffold afforded compounds 23 and 24 that were orally bioavailable, single-digit nanomolar FXIa inhibitors with excellent selectivity against relevant blood coagulation enzymes.
Organizational Affiliation:
Bristol-Myers Squibb Company, Research and Development, 350 Carter Road, Hopewell, NJ 08540, United States. Electronic address: [email protected].
