Identification of novel series of pyrazole and indole-urea based DFG-out PYK2 inhibitors

  • Bioorg Med Chem Lett. 2012 Dec 15;22(24):7523-9. doi: 10.1016/j.bmcl.2012.10.039.
Samit K Bhattacharya  1 ,  Gary E Aspnes ,  Scott W Bagley ,  Markus Boehm ,  Arthur D Brosius ,  Leonard Buckbinder ,  Jeanne S Chang ,  Joseph Dibrino ,  Heather Eng ,  Kosea S Frederick ,  David A Griffith ,  Matthew C Griffor ,  Cristiano R W Guimarães ,  Angel Guzman-Perez ,  Seungil Han ,  Amit S Kalgutkar ,  Jacquelyn Klug-McLeod ,  Carmen Garcia-Irizarry ,  Jianke Li ,  Blaise Lippa ,  David A Price ,  James A Southers ,  Daniel P Walker ,  Liuqing Wei ,  Jun Xiao ,  Michael P Zawistoski ,  Xumiao Zhao
Affiliations
  • 1. Worldwide Medicinal Chemistry, Pfizer Global Research and Development, 620 Memorial Drive, Cambridge, MA 02139, United States. [email protected]
PMID: 23153798 DOI: 10.1016/j.bmcl.2012.10.039
Abstract

Previous drug discovery efforts identified classical Pyk2 kinase inhibitors such as 2 and 3 that possess selectivity for Pyk2 over its intra-family isoform FAK. Efforts to identify more kinome-selective chemical matter that stabilize a DFG-out conformation of the enzyme are described herein. Two sub-series of Pyk2 inhibitors, an indole carboxamide-urea and a pyrazole-urea have been identified and found to have different binding interactions with the hinge region of Pyk2. These leads proved to be more selective than the original classical inhibitors.

Products