(407) Preclinical Evaluation of Human Somatostatin Receptor 4 (hSSTR4) Agonist CNTX-0290 for Mixed Pain Conditions

Abstract

CNTX-0290 is an oral, nonopioid hSSTR4 agonist under investigation for analgesia. Activity was assessed in acute, nociceptive, and neuropathic rat pain models. In the Complete Freund's Adjuvant (CFA) model, maximum efficacy of CNTX-0290 0.03–3 mg/kg vs vehicle was compared with indomethacin 30 mg/kg and celecoxib 10 mg/kg; minimal effective dose (MED) was determined. In the monosodium iodoacetate (MIA) osteoarthritis model, weight-bearing deficit (WBD) was assessed following CNTX-0290 0.01–30 mg/kg administration. Paw withdrawal threshold (PWT) was determined for CNTX-0290 0.03–0.3 mg/kg vs vehicle in the partial nerve ligation (PNL) model (control: lamotrigine 30 mg/kg) and at 3–30 mg/kg in the streptozocin diabetes model (control: duloxetine 30 mg/kg). In vitro potency and selectivity were evaluated. General/safety pharmacology studies were conducted in rats and cynomologus monkeys. Effects on growth hormone (GH) release and glucose tolerance were compared with octreotide. CNTX-0290 demonstrated potent, selective hSSTR4 agonism (EC50=2.6 nM; Ki=41 nM; hSSTR 1, 2, 3, and 5 Ki >10,000 nM). CNTX-0290 showed dose-dependent antinociceptive effects in the CFA model. Maximum efficacy was achieved at 3 mg/kg; MED was 0.1 mg/kg (minimal effective concentration [MEC]: 32 nM). In the MIA model, CNTX-0290 1–30 mg/kg significantly reversed WBD vs vehicle, and was comparable to morphine at 3 and 30 mg/kg. Efficacy up to 24 hours was observed in both models. In the PNL model, CNTX-0290 achieved maximum efficacy (comparable to lamotrigine) at 0.3 mg/kg; MED: 0.1 mg/kg (MEC: 25 nM). CNTX-0290 10 and 30 mg/kg significantly increased PWT vs vehicle in the streptozocin model, comparable to duloxetine. GH release and glucose tolerance were not significantly altered, and no dose-limiting CNS AEs were observed. CNTX-0290, a potent, selective, full hSSTR4 agonist, showed analgesic efficacy in models of nociceptive and neuropathic pain, demonstrating potential for treating mixed pain conditions. (Funding: Centrexion Therapeutics Corp.)