Pyridomycin bridges the NADH- and substratebinding pockets of the enoyl reductase InhA

Pyridomycin, a natural product with potent antituberculosis activity, inhibits a major drug target, the InhA enoyl reductase. Here, we unveil the co-crystal structure and unique ability of pyridomycin to block both the NADH cofactor- and lipid substrate-binding pockets of InhA. This is to our knowledge a first-of-a-kind binding mode that discloses a new means of InhA inhibition. Proof-of-principle studies show how structure-assisted drug design can improve the activity of new pyridomycin derivatives

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

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

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