934162-68-2Relevant 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.
1H-BENZIMIDAZOLE-4-CARBOXAMIDES SUBSTITUTED WITH PHENYL AT THE 2-POSITION ARE POTENT PARP INHIBITORS
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Page/Page column 47, (2010/11/26)
Compounds having formula (I), inhibit the PARP enzyme and are useful for treating a disease or a disorder associated with PARP. Also disclosed are pharmaceutical compositions comprising compounds having formula (I), methods of treatment comprising compounds having formula (I), and methods of inhibiting the PARP enzyme comprising compounds having formula (I).
