AZD9898 / AstraZeneca - LARVOL DELTA

Discovery of GJG057, a Potent and Highly Selective Inhibitor of Leukotriene C4 Synthase. (PubMed, J Med Chem) - "Herein, we disclose the discovery and preclinical profiling of the highly selective, oral LTC4S inhibitor GJG057 (compound 1), which exhibits 20-fold improved potency (IC50 = 44 nM) versus clinical candidate AZD9898 (IC50 = 900 nM) in a human whole blood LTC4 release assay...Despite its promising properties, GJG057 was not progressed into clinical trials as an oral drug. Its potential as a topical drug is currently being evaluated."

Journal • Asthma • Immunology • Inflammation • Pulmonary Disease • Respiratory Diseases

Discovery of the Oral Leukotriene-C4 Synthetase Inhibitor (1S,2S)-2-({5-[(5-Chloro-2,4-difluorophenyl)(2-fluoro-2-methylpropyl)amino]-3-methoxypyrazin-2-yl}carbonyl)cyclopropanecarboxylic acid (AZD9898) as a New Treatment for Asthma. (PubMed, J Med Chem) - "Starting from a screening hit 3, a program to discover oral inhibitors of LTC4S led to AZD9898 (36), a picomolar LTC4S inhibitor (IC50 = 0.28 nM) with high lipophilic ligand efficiency (LLE = 8.5), which displays nanomolar potency in cells (PBMC IC50,free = 6.2 nM) and good in vivo pharmacodynamics in a calcium ionophore stimulated rat model after oral dosing (in vivo IC50,free = 34 nM). Compound 36 mitigates the GABA binding, hepatic toxicity signal, and in vivo toxicology findings of an early lead compound 7, with a human dose predicted to 30 mg q.d."

Journal • Asthma • Respiratory Diseases