Modular Synthesis of Constrained Ethyl (cEt) Purine and Pyrimidine Nucleosides

A modular and scalable approach to pyrimidine- and purine-containing constrained ethyl (cEt) nucleosides is demonstrated. Minimizing stereochemical adjustments and protecting group manipulations, diacetone glucose is converted to two representative cEt nucleosides via a functionalized, common intermediate. The retrosynthetic approach to this complex class of drug precursors offers clear benefits over existing routes based on step count and efficiency

Optimization of a Novel Binding Motif to (<i>E</i>)‑3-(3,5-Difluoro-4-((1<i>R</i>,3<i>R</i>)‑2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro‑1<i>H</i>‑pyrido[3,4‑<i>b</i>]indol-1-yl)phenyl)acrylic Acid (AZD9496), a Potent and Orally Bioavailable Selective Estrogen Receptor Downregulator and Antagonist

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-1<i>H</i>-pyrido­[3,4-<i>b</i>]­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 (<i>E</i>)-3-(3,5-difluoro-4-((1<i>R</i>,3<i>R</i>)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1<i>H</i>-pyrido­[3,4-<i>b</i>]­indol-1-yl)­phenyl)­acrylic acid (<b>30b</b>, 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