Discovery and SAR of 2-(1-propylpiperidin-4-yl)-1H-benzimidazole-4-carboxamide: A potent inhibitor of poly(ADP-ribose) polymerase (PARP) for the treatment of cancer

  • Bioorg Med Chem. 2008 Jul 15;16(14):6965-75. doi: 10.1016/j.bmc.2008.05.044.
Thomas D Penning  1 ,  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
Affiliations
  • 1. Cancer Research, GPRD, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064, USA. [email protected]
PMID: 18541433 DOI: 10.1016/j.bmc.2008.05.044
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.

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