2. Academic Validation
  3. 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

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

  • J Med Chem. 2010 Apr 22;53(8):3142-53. doi: 10.1021/jm901775y.
Thomas D Penning 1,  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
Affiliations

Affiliation

  • 1 Cancer Research, Abbott Laboratories 100 Abbott Park Road, Abbott Park, Illinois 60064, USA. thomas.penning@abbott.com
PMID: 20337371 DOI: 10.1021/jm901775y
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-10614
    99.95%, PARP1/2 Inhibitor