Discovery of N-(4-methoxyphenyl)-N,2-dimethylquinazolin-4-amine, a potent apoptosis inducer and efficacious anticancer agent with high blood brain barrier penetration

  • J Med Chem. 2009 Apr 23;52(8):2341-51. doi: 10.1021/jm801315b.
Nilantha Sirisoma  1 ,  Azra Pervin ,  Hong Zhang ,  Songchun Jiang ,  J Adam Willardsen ,  Mark B Anderson ,  Gary Mather ,  Christopher M Pleiman ,  Shailaja Kasibhatla ,  Ben Tseng ,  John Drewe ,  Sui Xiong Cai
Affiliations
  • 1. EpiCept Corporation, 6650 Nancy Ridge Drive, San Diego, California 92121, USA.
PMID: 19296653 DOI: 10.1021/jm801315b
Abstract

As a continuation of our structure-activity relationship (SAR) studies on 4-anilinoquinazolines as potent Apoptosis inducers and to identify Anticancer development candidates, we explored the replacement of the 2-Cl group in our lead compound 2-chloro-N-(4-methoxyphenyl)-N-methylquinazolin-4-amine (6b, EP128265, MPI-0441138) by Other functional groups. This SAR study and lead optimization resulted in the identification of N-(4-methoxyphenyl)-N,2-dimethylquinazolin-4-amine (6h, EP128495, MPC-6827) as an Anticancer clinical candidate. Compound 6h was found to be a potent Apoptosis Inducer with EC(50) of 2 nM in our cell-based Apoptosis induction assay. It also has excellent blood brain barrier penetration, and is highly efficacious in human MX-1 breast and Other mouse xenograft Cancer models.

Products