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Tetrahydroisoquinoline Phenols: Selective Estrogen Receptor Downregulator Antagonists with Oral Bioavailability in Rat

DOI: 10.1021/acsmedchemlett.5b00413 DOI Help
PMID: 26819673 PMID Help

Authors: James S. Scott (AstraZeneca) , Andrew Bailey (AstraZeneca) , Robert D. M. Davies (AstraZeneca) , S├ębastien L. Degorce (AstraZeneca) , Philip A. Macfaul (AstraZeneca) , Helen Gingell (AstraZeneca) , Thomas Moss (AstraZeneca) , Richard A. Norman (AstraZeneca) , Jennifer H. Pink (AstraZeneca) , Alfred A. Rabow (AstraZeneca) , Bryan Roberts (AstraZeneca) , Peter D. Smith (AstraZeneca)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Acs Medicinal Chemistry Letters , VOL 7 , PAGES 94 - 99

State: Published (Approved)
Published: January 2016

Abstract: A series of tetrahydroisoquinoline phenols was modified to give an estrogen receptor downregulator-antagonist profile. Optimization around the core, alkyl side chain, and pendant aryl ring resulted in compounds with subnanomolar levels of potency. The phenol functionality was shown to be required to achieve highly potent compounds, but unusually this was compatible with obtaining high oral bioavailabilities in rat.

Subject Areas: Biology and Bio-materials


Instruments: I04-1-Macromolecular Crystallography (fixed wavelength)