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

Abstract

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.

Novel Selective Estrogen Receptor Downregulators (SERDs) Developed against Treatment-Resistant Breast Cancer

“…22 The discovery of a further next generation SERD, 4 , resulted from a high-throughput screening campaign: 4 contains a 1-aryl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole scaffold, apparently devoid of any hydrogen-bonding interactions with either Glu353 or Arg394, and with a good pharmacokinetic profile. 24 Both 2 and 4 were reported to have physicochemical properties superior to 1 and are actively being studied in clinical trials. 20, 24, 25, 63 …”

“…24 Both 2 and 4 were reported to have physicochemical properties superior to 1 and are actively being studied in clinical trials. 20, 24, 25, 63 …”

“…15–17 The clinical efficacy of 1 , despite its poor physicochemical and pharmacokinetic characteristics, has inspired contemporary interest in orally bioavailable SERDs. The recent intensive interest in discovery and development of novel orally bioavailable SERDs is highlighted by the pursuit of SERDs on multiple scaffolds 18–21 , and the clinical development of GDC-0810 (ARN-810, 2 ) 22 , RAD-1901 23 , and AZD-9496 ( 4 ) 24, 25 by Genentech, Radius Health, and Astra Zeneca, respectively.…”

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

“…Structures of 11a and 12 (Figure 2b) showed minimal perturbation of the tetrahydroisoquinoline phenol with the 3-(R)-methyl group filling the "Phe-404:Phe-425 lipophilic hole" as described previously. 7 Methyl substitution ortho to the phenol led to a reduction in potency, more marked in the 5-methyl (15) than the 7-methyl (16) compound. This was consistent with a significant shift in the position of the core to accommodate the 5-methyl substitution as shown in Figure 2c and a corresponding lengthening of the interactions of the phenol with the water and salt bridge (3.6/2.7/3.6 Å).…”

“…7 We initially looked to reduce lipophilicity by introduction of an ether to the 3-position of the N-alkyl chain (19). This resulted in a lowering of logD (ΔlogD 7.4 − 0.7 relative to 12) and reduced the amount of GSH trapping observed but was lower in potency.…”