Optimization of phenyl-substituted benzimidazole carboxamide poly(ADP-ribose) polymerase inhibitors: identification of (S)-2-(2-fluoro-4-(pyrrolidin-2-yl)phenyl)-1H-benzimidazole-4-carboxamide (A-966492), a highly potent and efficacious inhibitor.

Abstract

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 K(i) of 1 nM and an EC(50) 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.

• Authors: Thomas D Penning, Gui-Dong Zhu, Jianchun Gong, Sheela Thomas, Viraj B Gandhi, Xuesong Liu, Yan Shi, Vered Klinghofer, Eric F Johnson, Chang H Park, Elizabeth H Fry, Cherrie K Donawho, David J Frost, Fritz G Buchanan, Gail T Bukofzer, Luis E Rodriguez, Velitchka Bontcheva-Diaz, Jennifer J Bouska, Donald J Osterling, Amanda M Olson, Kennan C Marsh, Yan Luo, Vincent L Giranda
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 53 Issue 8 Pg. 3142-53 (Apr 22 2010) ISSN: 1520-4804 [Electronic] United States
• PMID: 20337371 (Publication Type: Journal Article)

Chemical References

• 2-(2-fluoro-4-(pyrrolidin-2-yl)phenyl)-1H-benzimidazole-4-carboxamide
• Antineoplastic Agents
• BRCA1 Protein
• Benzimidazoles
• Poly(ADP-ribose) Polymerase Inhibitors
• Dacarbazine
• Carboplatin
• Temozolomide

Topics

• Animals
• Antineoplastic Agents (chemical synthesis, pharmacology, therapeutic use)
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• BRCA1 Protein (deficiency)
• Benzimidazoles (chemical synthesis, pharmacology, therapeutic use)
• Biological Availability
• Blood-Brain Barrier (metabolism)
• Carboplatin (administration & dosage)
• Cell Line, Tumor
• Crystallography, X-Ray
• Dacarbazine (administration & dosage, analogs & derivatives)
• Drug Screening Assays, Antitumor
• Female
• Melanoma, Experimental (drug therapy)
• Mice
• Mice, Inbred C57BL
• Mice, SCID
• Models, Molecular
• Neoplasm Transplantation
• Poly(ADP-ribose) Polymerase Inhibitors
• Stereoisomerism
• Structure-Activity Relationship
• Temozolomide
• Transplantation, Heterologous