Optimization of a Novel Binding Motif 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 (AZD9496), a Potent and O

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• 作者：Chris De Savi ; Robert H. Bradbury ; Alfred A. Rabow ; Richard A. Norman ; Camila de Almeida ; David M. Andrews ; Peter Ballard ; David Buttar ; Rowena J. Callis ; Gordon S. Currie ; Jon O. Curwen ; Chris D. Davies ; Craig S. Donald ; Lyman J. L. Feron ; Helen Gingell ; Steven C. Glossop ; Barry R. Hayter ; Syeed Hussain ; Galith Karoutchi ; Scott G. Lamont ; Philip MacFaul ; Thomas A. Moss ; Stuart E. Pearson ; Michael Tonge ; Graeme E. Walker ; Hazel M. Weir ; Zena Wilson
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：October 22, 2015
• 年：2015
• 卷：58
• 期：20
• 页码：8128-8140
• 全文大小：637K
• ISSN：1520-4804

文摘

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.