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1. Optimization of Novel Acyl Pyrrolidine Inhibitors of Hepatitis C Virus RNA-Dependent RNA Polymerase Leading to a Development Candidate.

Author

Martin J. Slater, Elizabeth M. Amphlett, David M. Andrews, Gianpaolo Bravi, George Burton, Anne G. Cheasty, John A. Corfield, Malcolm R. Ellis, Rebecca H. Fenwick, Stephanie Fernandes, Rossella Guidetti, David Haigh, C. David Hartley, Peter D. Howes, Deborah L. Jackson, Richard L. Jarvest, Victoria L. H. Lovegrove, Katrina J. Medhurst, Nigel R. Parry, and Helen Price

Subjects
*PYRROLIDINE, *RNA polymerases, *HEPATITIS C virus, *PHARMACOKINETICS
Abstract

Optimization of a pyrrolidine-based template using structure-based design and physicochemical considerations has provided a development candidate 20b(3082) with submicromolar potency in the HCV replicon and good pharmacokinetic properties. [ABSTRACT FROM AUTHOR]

Published
2007
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2. Optimization ofa 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)acrylicAcid (AZD9496), a Potent and Orally Bioavailable Selective EstrogenReceptor Downregulator and Antagonist

Author

Chris De Savi, Robert H. Bradbury, AlfredA. 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, and Scott G. Lamont

Subjects
*SELECTIVE estrogen receptor modulators, *DRUG bioavailability, *PHARMACEUTICAL chemistry, *DIFLUOROMETHYL compounds, *LIGANDS (Biochemistry), *BREAST cancer treatment
Abstract

Thediscovery of an orally bioavailable selective estrogen receptordownregulator (SERD) with equivalent potency and preclinical pharmacologyto the intramuscular SERD fulvestrant is described. A directed screenidentified the 1-aryl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole motif as a novel, druglike ER ligand. Aided bycrystal structures of novel ligands bound to an ER construct, medicinalchemistry 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)acrylicacid (30b, AZD9496), a clinical candidate with high oralbioavailability across preclinical species that is currently beingevaluated in phase I clinical trials for the treatment of advancedestrogen receptor (ER) positive breast cancer. [ABSTRACT FROM AUTHOR]

Published
2015
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