1128075-42-2Relevant academic research and scientific papers
Optimization of phenyl-substituted benzimidazole carboxamide poly(ADP-ribose) polymerase inhibitors: Identification of (S)-2-(2-fluoro-4- (pyrrolidin-2-yl)phenyl)-1 H -benzimidazole-4-carboxamide (A-966492), a highly potent and efficacious inhibitor
Penning, Thomas D.,Zhu, Gui-Dong,Gong, Jianchun,Thomas, Sheela,Gandhi, Viraj B.,Liu, Xuesong,Shi, Yan,Klinghofer, Vered,Johnson, Eric F.,Park, Chang H.,Fry, Elizabeth H.,Donawho, Cherrie K.,Frost, David J.,Buchanan, Fritz G.,Bukofzer, Gail T.,Rodriguez, Luis E.,Bontcheva-Diaz, Velitchka,Bouska, Jennifer J.,Osterling, Donald J.,Olson, Amanda M.,Marsh, Kennan C.,Luo, Yan,Giranda, Vincent L.
experimental part, p. 3142 - 3153 (2010/09/18)
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 Ki of 1 nM and an EC50 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.
