SRX246 is a centrally penetrant vasopressin 1a (V1a) receptor antagonist[1-2]. SRX246 has potential applications in treating stress-related disorders and irritability in patients with Huntington's disease[3-4].
In vivo, Beagle dogs were orally administered SRX246 (3, 15, and 75mg/kg) once daily for 28 consecutive days. The oral bioavailability of SRX246 in Beagle dogs was approximately 11%. The plasma exposure (AUC and Cmax) of SRX246 increased with the dose, and no significant toxicity was observed during the 28-day dosing study[5]. In rats, a single oral dose of SRX246 (20mg/kg) was administered. The maximum plasma concentration (Cmax) reached 100ng/ml, with a time to peak (Tmax) of 4 hours and a plasma half-life (T1/2) of 2.5 hours. SRX246 effectively penetrated the blood-brain barrier. The maximum concentration of SRX246 in brain tissue was 20ng/ml, and SRX246 half-life in the brain was approximately 6 hours[6].
References:
[1] Maibach HT, Brownstein MJ, Hersch SM, et al. The Vasopressin 1a Receptor Antagonist SRX246 Reduces Aggressive Behavior in Huntington's Disease. Journal of Personalized Medicine. 2022 Sep;12(10):1561.
[2] Norred MA, Zuschlag ZD, Hamner MB. A Neuroanatomic and Pathophysiologic Framework for Novel Pharmacological Approaches to the Treatment of Post-traumatic Stress Disorder. Drugs. 2024 Feb;84(2):149-164.
[3] Andriessen RL, Oosterloo M, Molema J, et al. Pharmacological Treatment of Neuropsychiatric Symptoms in Huntington's Disease: A Systematic Review. Movement Disorders Clinical Practice. 2025 Apr;12(4):418-431.
[4] Difede J, McAleavey AA, Emrich M, et al. A proof-of-concept randomized crossover clinical trial of a first-in-class vasopressin 1a receptor antagonist for PTSD: Design, methods, and recruitment. Contemporary Clinical Trials Communications. 2023 Jun;33:101116.
[5] Fabio KM, Guillon CD, Lu SF, et al. Pharmacokinetics and metabolism of SRX246: a potent and selective vasopressin 1a antagonist. J Pharm Sci. 2013 Jun;102(6):2033-2043.
[6] Guillon CD, Koppel GA, Brownstein MJ, et al. Azetidinones as vasopressin V1a antagonists. Bioorg Med Chem. 2007 Mar 1;15(5):2054-80.
SRX246是一种强效的、具有中枢神经系统穿透性的血管加压素1a（V1a）受体拮抗剂[1-2]。SRX246可用于治疗与压力有关的疾病和亨廷顿病患者的易激惹性[3-4]。
在体内，口服SRX246（3，15，75mg/kg）处理Beagle Dogs，每日次，连续28天，Beagle Dogs对SRX246的生物利用度约为11%，SRX246的血浆暴露量（AUC和Cmax）随剂量增加而增加，在28天给药研究中未观察到显著的毒性反应[5]。大鼠口服给药SRX246（20mg/kg），SRX246在血浆中的最大浓度为100ng/ml，达峰时间（Tmax）为4小时，血浆半衰期（T1/2）为2.5小时。SRX246能有效穿透血脑屏障。SRX246在脑组织中的最大浓度为20ng/ml，脑内半衰期约为6小时[6]。