Discovery of LXR Modulator WAY-252623

MEDI 468

Jay Wrobel, wrobelj@wyeth.com1, Robert J. Steffan1, Edward Matelan1, Stephen Marc Bowen, bowens@wyeth.com1, Baihua Hu1, Michael Collini1, Christopher P Miller1, Ray J Unwalla1, Ponnal Nambi2, Elaine Quinet2, Liang Chen2, Anita Halpern2, Qiang-Yuan Liu2, Dawn Savio2, Eduoard Zamaratsky3, Lars Kruger3, Anna Wilhelmsson3, Annika Goos Nilsson3, Crina Ursu3, Erik Arnelof3, Johnny Sandberg3, Christopher Enroth3, Tomas Bonn3, and Mathias Farnegardh3. (1) Chemical and Screening Sciences, Wyeth Research, 500 Arcola Road, Collegeville, PA 19426, (2) Department of Cardiovascular and Metabolic Diseases, Wyeth Research, 500 Arcola Rd, Collegeville, PA 19426, (3) Karo Bio AB, SE-141 57, Huddinge, Sweden
Liver X-Receptors (LXRa and LXRb ) are members of the nuclear hormone receptor family of ligand-activated transcription factors that form obligate heterodimers with retinoid X receptors. LXRs act as a transcriptional master switches that coordinate the regulation of gene expression involved in cellular cholesterol homeostasis. LXR regulation of ABCA1, CETP, ApoE and several other key genes that mediate reverse cholesterol transport (RCT), validate LXR as a therapeutic target to promote RCT from atherosclerotic coronary lesions. Unfortunately, known LXR modulators share the undesirable side-effects of inducing hypertriglyceridemia by transactivating genes in the liver involved in fatty acid biosynthesis, including sterol regulatory binding element protein 1c (SREBP-1c) and fatty acid synthase (FAS). The pharmacological challenge therefore, is to identify LXR modulators that selectively activate desirable LXR target genes. The discovery, SAR and in vitro biology of a new LXR modulator WAY-252623 with minimal effects on triglycerides will be described.
 

General Oral Session
1:30 PM-4:50 PM, Thursday, August 23, 2007 BCEC -- 210A, Oral

Division of Medicinal Chemistry

The 234th ACS National Meeting, Boston, MA, August 19-23, 2007