A high throughput, automated chemistry approach to the lead optimization of novel P38 MAP kinase inhibitors derived from 1,4-disubstituted naphthalenes

MEDI 198

Hui Wu1, Mark A. Ashwell, Yanbin Liu, yliu@arqule.com1, Syed M. Ali, sali@arqule.com2, Jason Hill2, and Woj Wrona3. (1) Medicinal Chemistry, ArQule Inc, 19 Presidential Way, Woburn, 01801, (2) R&D Chemistry, ArQule Inc, 19 Presidential Way, Woburn, MA 01801, (3) Novartis, Cambridge, MA
A novel series of orally bioavailable, small-molecule, p38 mitogen-activated protein (MAP) kinase inhibitors have been elaborated from a 1,4-disubstituted naphthalene1 template. A high throughput automated chemistry strategy was employed in the lead optimization stage of the project. Two series of high quality compound libraries will be described which provided changes to key structural features. These synthetic approaches and the resulting SAR for the inhibitory activity against p38á kinase and TNFá release in THP-1 cells will be described.

Figure 1:

 

General Poster Session
7:00 PM-9:00 PM, Sunday, 10 September 2006 Moscone Center -- Hall D, Poster

Sci-Mix
8:00 PM-10:00 PM, Monday, 11 September 2006 Moscone Center -- Hall D, Sci-Mix

Division of Medicinal Chemistry

The 232nd ACS National Meeting, San Francisco, CA, September 10-14, 2006