Download MendeleyOptimization of phenyl-substituted benzimidazole carboxamide poly(ADP-ribose) polymerase inhibitors: identification of (S)-2-(2-fluoro-4-(pyrrolidin-2-yl)phenyl)-1H-benzimidazole-4-carboxamide (A-966492), a highly potent and efficacious inhibitor.
Penning, T.D., Zhu, G.D., Gong, J., Thomas, S., Gandhi, V.B., Liu, X., Shi, Y., Klinghofer, V., Johnson, E.F., Park, C.H., Fry, E.H., Donawho, C.K., Frost, D.J., Buchanan, F.G., Bukofzer, G.T., Rodriguez, L.E., Bontcheva-Diaz, V., Bouska, J.J., Osterling, D.J., Olson, A.M., Marsh, K.C., Luo, Y., Giranda, V.L.(2010) J Med Chem 53: 3142-3153
- PubMed: 20337371
- DOI: https://doi.org/10.1021/jm901775y
- Primary Citation of Related Structures:
3L3M - PubMed Abstract:
We have developed a series of phenylpyrrolidine- and phenylpiperidine-substituted benzimidazole carboxamide poly(ADP-ribose) polymerase (PARP) inhibitors with excellent PARP enzyme potency as well as single-digit nanomolar cellular potency. These efforts led to the identification of (S)-2-(2-fluoro-4-(pyrrolidin-2-yl)phenyl)-1H-benzimidazole-4-carboxamide (22b, A-966492). Compound 22b displayed excellent potency against the PARP-1 enzyme with a K(i) of 1 nM and an EC(50) of 1 nM in a whole cell assay. In addition, 22b is orally bioavailable across multiple species, crosses the blood-brain barrier, and appears to distribute into tumor tissue. It also demonstrated good in vivo efficacy in a B16F10 subcutaneous murine melanoma model in combination with temozolomide and in an MX-1 breast cancer xenograft model both as a single agent and in combination with carboplatin.
Organizational Affiliation:
Cancer Research, Abbott Laboratories 100 Abbott Park Road, Abbott Park, Illinois 60064, USA. [email protected]
