| Literature DB >> 26407012 |
Chris De Savi1,2, Robert H Bradbury1, Alfred A Rabow1, Richard A Norman3, Camila de Almeida1, David M Andrews1, Peter Ballard1, David Buttar1, Rowena J Callis3, Gordon S Currie1, Jon O Curwen1, Chris D Davies1, Craig S Donald1, Lyman J L Feron1, Helen Gingell3, Steven C Glossop1, Barry R Hayter1, Syeed Hussain3, Galith Karoutchi1, Scott G Lamont1, Philip MacFaul1, Thomas A Moss1, Stuart E Pearson1, Michael Tonge3, Graeme E Walker3, Hazel M Weir1, Zena Wilson1.
Abstract
The discovery of an orally bioavailable selective estrogen receptor downregulator (SERD) with equivalent potency and preclinical pharmacology to the intramuscular SERD fulvestrant is described. A directed screen identified the 1-aryl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole motif as a novel, druglike ER ligand. Aided by crystal structures of novel ligands bound to an ER construct, medicinal chemistry iterations led to (E)-3-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylic acid (30b, AZD9496), a clinical candidate with high oral bioavailability across preclinical species that is currently being evaluated in phase I clinical trials for the treatment of advanced estrogen receptor (ER) positive breast cancer.Entities:
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Year: 2015 PMID： 26407012 DOI： 10.1021/acs.jmedchem.5b00984
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446