| Literature DB >> 18541433 |
Thomas D Penning1, Gui-Dong Zhu, Viraj B Gandhi, Jianchun Gong, Sheela Thomas, Wilfried Lubisch, Roland Grandel, Wolfgang Wernet, Chang H Park, Elizabeth H Fry, Xuesong Liu, Yan Shi, Vered Klinghofer, Eric F Johnson, Cherrie K Donawho, David J Frost, Velitchka Bontcheva-Diaz, Jennifer J Bouska, Amanda M Olson, Kennan C Marsh, Yan Luo, Saul H Rosenberg, Vincent L Giranda.
Abstract
We have developed a series of cyclic amine-containing benzimidazole carboxamide poly(ADP-ribose)polymerase (PARP) inhibitors, with good PARP-1 enzyme potency, as well as cellular potency. These efforts led to the identification of a lead preclinical candidate, 10b, 2-(1-propylpiperidin-4-yl)-1H-benzimidazole-4-carboxamide (A-620223). 10b displayed very good potency against both the PARP-1 enzyme with a K(i) of 8nM and in a whole cell assay with an EC(50) of 3nM. 10b is aqueous soluble, orally bioavailable across multiple species, and demonstrated good in vivo efficacy in a B16F10 subcutaneous murine melanoma model in combination with temozolomide (TMZ) and in an MX-1 breast xenograph model in combination with cisplatin.Entities:
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Year: 2008 PMID： 18541433 DOI： 10.1016/j.bmc.2008.05.044
Source DB: PubMed Journal: Bioorg Med Chem ISSN： 0968-0896 Impact factor: 3.641