Structure–Activity Relationships and Discovery of a G Protein Biased μ Opioid Receptor Ligand, [(3-Methoxythiophen-2-yl)methyl]({2-[(9R)‑9-(pyridin-2-yl)-6-oxaspiro-[4.5]decan-9-yl]ethyl})amine (TRV130), for the Treatment of Acute Severe Pain

• Published in: Journal of medicinal chemistry 2013-10, Vol.56 (20), p.8019-8031
• Main Authors: Chen, Xiao-Tao, Pitis, Philip, Liu, Guodong, Yuan, Catherine, Gotchev, Dimitar, Cowan, Conrad L, Rominger, David H, Koblish, Michael, DeWire, Scott M, Crombie, Aimee L, Violin, Jonathan D, Yamashita, Dennis S
• Format: Article
• Language: English
• Subjects: Acute Pain - drug therapy; Acute Pain - pathology; Analgesics - chemical synthesis; Analgesics - chemistry; Analgesics - pharmacology; Animals; Disease Models, Animal; Drug Discovery - methods; GTP-Binding Proteins - metabolism; HEK293 Cells; Humans; Mice; Models, Chemical; Molecular Structure; Rats; Receptors, Opioid, mu - agonists; Receptors, Opioid, mu - metabolism; Severity of Illness Index; Spiro Compounds - chemical synthesis; Spiro Compounds - chemistry; Spiro Compounds - pharmacology; Structure-Activity Relationship; Thiophenes - chemical synthesis; Thiophenes - chemistry; Thiophenes - pharmacology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm4010829

The concept of “ligand bias” at G protein coupled receptors has been introduced to describe ligands which preferentially stimulate one intracellular signaling pathway over another. There is growing interest in developing biased G protein coupled receptor ligands to yield safer, better tolerated, and more efficacious drugs. The classical μ opioid morphine elicited increased efficacy and duration of analgesic response with reduced side effects in β-arrestin-2 knockout mice compared to wild-type mice, suggesting that G protein biased μ opioid receptor agonists would be more efficacious with reduced adverse events. Here we describe our efforts to identify a potent, selective, and G protein biased μ opioid receptor agonist, TRV130 (( R )-30). This novel molecule demonstrated an improved therapeutic index (analgesia vs adverse effects) in rodent models and characteristics appropriate for clinical development. It is currently being evaluated in human clinical trials for the treatment of acute severe pain.