Discovery of pyrazole‐1‐carboxamide derivatives as novel Gi‐biased μ‐opioid receptor agonists

Abstract

μ-Opioid receptor (MOR) Gi-biased agonists with no recruitment of β-arrestin were introduced as a new analgesic strategy to overcome the conventional undesirable side effects of opioid receptor-targeted drugs, such as tolerance, addiction, respiratory depression, and constipation. For the development of novel Gi-biased MOR agonists, the design, synthesis, and structure-activity relationship (SAR) analysis of the aminopyrazole core skeleton were conducted according to the current SAR data of PZM21 (2a) and its derivatives. New derivatives were biologically evaluated for their agonistic effects on cyclic adenosine monophosphate (cAMP) levels for the Gi pathway and β-arrestin recruitment in MOR/κ-opioid receptor/δ opioid receptor. An optimized selective Gi-biased agonist, Compound 17a, was discovered with potent cAMP inhibitory activities, with a 50% efficacy concentration value of 87.1 nM and no activity in the MOR β-arrestin pathway and other subtypes. The in vivo pain relief efficacy of Compound 17a was confirmed in a dose-dependent manner with spinal nerve ligation and cisplatin-induced peripheral neuropathy rodent neuropathic pain models.analgesics, Gi-biased MOR agonist, pyrazole-1-carboxamide derivatives | INTRODUCTIONμ-Opioid receptor (MOR)-targeted drugs, such as morphine and fentanyl, known to possess the highest analgesic medicinal efficacies, have been commonly used as medications to manage moderate to severe pain (Melnikova, 2010). However, medical use of these drugs should be tightly regulated due to the accompanying undesirable side effects because the analgesic effects are derived from the activation of opioid receptors present in the central nervous system (Listos

Electrochemically enabled oxidative aromatization of pyrazolines

“…2 One prominent example is sildenafil ( 3 ), a phosphodiesterase inhibitor for treatment of erectile dysfunction (Chart 1). Furthermore, pyrazoles exhibit metabolic, 3 cardiac, 4 and gastrointestinal effects, 5 antibacterial, 6 antipsychotic, 7 anti-inflammatory, 8 antinociceptive 9 properties and are promising candidates for the development of new anticancer drugs. 10 Pyrazoles are widely found in active compounds in agrochemicals, e.g.…”