2. Academic Validation
  3. 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

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

Affiliation

  • 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.

Figures
Products