[Show abstract][Hide abstract] ABSTRACT: The discovery and optimization of a series of 4-aminocinnoline-3-carboxamide inhibitors of Bruton's tyrosine kinase are reported. A fragment-based screening approach incorporating X-ray co-crystallography was used to identify a cinnoline fragment and characterize its binding mode in the ATP binding site of Btk. Optimization of the fragment hit resulted in the identification of a lead compound which reduced paw swelling in a dose- and exposure-dependent fashion in a rat model of collagen-induced arthritis.
No preview · Article · Jun 2015 · Journal of Medicinal Chemistry
[Show abstract][Hide abstract] ABSTRACT: The structure-based design, synthesis, and biological evaluation of two novel series of potent and selective MEK kinase inhibitors are described herein. The elaboration of a lead pyrrole derivative to a bicyclic dihydroindolone core provided compounds with high potency and good drug-like pharmaceutical properties. Further scaffold modification afforded a series of dihydroindolizinone inhibitors, including an orally available advanced preclinical MEK inhibitor with potent in vivo antitumor efficacy.
No preview · Article · Feb 2012 · Bioorganic & medicinal chemistry letters
[Show abstract][Hide abstract] ABSTRACT: A novel 5-phenylamino-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione series of MEK inhibitors has been developed using structure-based drug design. Lead optimization of this series led to the discovery of TAK-733. This was advanced to Phase I clinical studies for cancer treatment.
No preview · Article · Mar 2011 · Bioorganic & medicinal chemistry letters
[Show abstract][Hide abstract] ABSTRACT: A novel, efficient route for the synthesis of 1,8-naphthyridine-2,5-dione compounds is reported. The synthetic scheme allows for diversification at the 4-position of the core, and it was utilized to develop a series of inhibitors for MEK kinase.
No preview · Article · Jan 2011 · Tetrahedron Letters
[Show abstract][Hide abstract] ABSTRACT: A novel series of pyrrole inhibitors of MEK kinase has been developed using structure-based drug design. Optimization of the series led to the identification of potent inhibitors with good pharmaceutical properties.