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 Orally Bioavailable Selective Estrogen Receptor Downregulator and Antagonist.

Autor: De Savi C; Oncology iMed, AstraZeneca, Mereside, Alderley Park, Macclesfield SK10 4TG, U.K.; Oncology iMed, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States., Bradbury RH; Oncology iMed, AstraZeneca, Mereside, Alderley Park, Macclesfield SK10 4TG, U.K., Rabow AA; Oncology iMed, AstraZeneca, Mereside, Alderley Park, Macclesfield SK10 4TG, U.K., Norman RA; Discovery Sciences, AstraZeneca, Mereside, Alderley Park, Macclesfield SK10 4TG, U.K., de Almeida C; Oncology iMed, AstraZeneca, Mereside, Alderley Park, Macclesfield SK10 4TG, U.K., Andrews DM; Oncology iMed, AstraZeneca, Mereside, Alderley Park, Macclesfield SK10 4TG, U.K., Ballard P; Oncology iMed, AstraZeneca, Mereside, Alderley Park, Macclesfield SK10 4TG, U.K., Buttar D; Oncology iMed, AstraZeneca, Mereside, Alderley Park, Macclesfield SK10 4TG, U.K., Callis RJ; Discovery Sciences, AstraZeneca, Mereside, Alderley Park, Macclesfield SK10 4TG, U.K., Currie GS; Oncology iMed, AstraZeneca, Mereside, Alderley Park, Macclesfield SK10 4TG, U.K., Curwen JO; Oncology iMed, AstraZeneca, Mereside, Alderley Park, Macclesfield SK10 4TG, U.K., Davies CD; Oncology iMed, AstraZeneca, Mereside, Alderley Park, Macclesfield SK10 4TG, U.K., Donald CS; Oncology iMed, AstraZeneca, Mereside, Alderley Park, Macclesfield SK10 4TG, U.K., Feron LJ; Oncology iMed, AstraZeneca, Mereside, Alderley Park, Macclesfield SK10 4TG, U.K., Gingell H; Discovery Sciences, AstraZeneca, Mereside, Alderley Park, Macclesfield SK10 4TG, U.K., Glossop SC; Oncology iMed, AstraZeneca, Mereside, Alderley Park, Macclesfield SK10 4TG, U.K., Hayter BR; Oncology iMed, AstraZeneca, Mereside, Alderley Park, Macclesfield SK10 4TG, U.K., Hussain S; Discovery Sciences, AstraZeneca, Mereside, Alderley Park, Macclesfield SK10 4TG, U.K., Karoutchi G; Oncology iMed, AstraZeneca, Mereside, Alderley Park, Macclesfield SK10 4TG, U.K., Lamont SG; Oncology iMed, AstraZeneca, Mereside, Alderley Park, Macclesfield SK10 4TG, U.K., MacFaul P; Oncology iMed, AstraZeneca, Mereside, Alderley Park, Macclesfield SK10 4TG, U.K., Moss TA; Oncology iMed, AstraZeneca, Mereside, Alderley Park, Macclesfield SK10 4TG, U.K., Pearson SE; Oncology iMed, AstraZeneca, Mereside, Alderley Park, Macclesfield SK10 4TG, U.K., Tonge M; Discovery Sciences, AstraZeneca, Mereside, Alderley Park, Macclesfield SK10 4TG, U.K., Walker GE; Discovery Sciences, AstraZeneca, Mereside, Alderley Park, Macclesfield SK10 4TG, U.K., Weir HM; Oncology iMed, AstraZeneca, Mereside, Alderley Park, Macclesfield SK10 4TG, U.K., Wilson Z; Oncology iMed, AstraZeneca, Mereside, Alderley Park, Macclesfield SK10 4TG, U.K.
Jazyk: angličtina
Zdroj: Journal of medicinal chemistry [J Med Chem] 2015 Oct 22; Vol. 58 (20), pp. 8128-40. Date of Electronic Publication: 2015 Oct 07.
DOI: 10.1021/acs.jmedchem.5b00984
Abstrakt: 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.
Databáze: MEDLINE
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