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.

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.

• Authors: Thomas D Penning, 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
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 16 Issue 14 Pg. 6965-75 (Jul 15 2008) ISSN: 1464-3391 [Electronic] England
• PMID: 18541433 (Publication Type: Journal Article)

Chemical References

• Benzimidazoles
• Enzyme Inhibitors
• Poly(ADP-ribose) Polymerase Inhibitors
• Dacarbazine
• Cisplatin
• Temozolomide

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Benzimidazoles (chemistry, pharmacology)
• Breast Neoplasms (drug therapy)
• Cisplatin (therapeutic use)
• Dacarbazine (analogs & derivatives, therapeutic use)
• Enzyme Inhibitors (chemistry, pharmacology)
• Humans
• Melanoma, Experimental (drug therapy)
• Mice
• Poly(ADP-ribose) Polymerase Inhibitors
• Structure-Activity Relationship
• Temozolomide
• Transplantation, Heterologous
• Xenograft Model Antitumor Assays