Academy of Scientific and Innovative Research (AcSIR) , New Delhi 110001 , India.
National Institute of Pharmaceutical Education and Research Raebareli , New Transit Campus, Bijnor Road , Sarojani Nagar, Near CRPF Base Camp, Lucknow , 226002 Uttar Pradesh , India.
J Med Chem. 2019 May 9;62(9):4638-4655. doi: 10.1021/acs.jmedchem.9b00241. Epub 2019 Apr 29.
The histamine 3 receptor (H3R) is a presynaptic receptor, which modulates several neurotransmitters including histamine and various essential physiological processes, such as feeding, arousal, cognition, and pain. The H3R is considered as a drug target for the treatment of several central nervous system disorders. We have synthesized and identified a novel series of 4-aryl-6-methyl-5,6,7,8-tetrahydroquinazolinamines that act as selective H3R antagonists. Among all the synthesized compounds, in vitro and docking studies suggested that the 4-methoxy-phenyl-substituted tetrahydroquinazolinamine compound 4c has potent and selective H3R antagonist activity (IC < 0.04 μM). Compound 4c did not exhibit any activity on the hERG ion channel and pan-assay interference compounds liability. Pharmacokinetic studies showed that 4c crosses the blood brain barrier, and in vivo studies demonstrated that 4c induces anorexia and weight loss in obese, but not in lean mice. These data reveal the therapeutic potential of 4c as an anti-obesity candidate drug via antagonizing the H3R.
组胺 3 受体（H3R）是一种突触前受体，调节包括组胺在内的多种神经递质和各种基本生理过程，如进食、觉醒、认知和疼痛。H3R 被认为是治疗多种中枢神经系统疾病的药物靶点。我们合成并鉴定了一系列新型的 4-芳基-6-甲基-5,6,7,8-四氢喹唑啉胺，它们作为选择性 H3R 拮抗剂。在所有合成的化合物中，体外和对接研究表明，4-甲氧基-苯基取代的四氢喹唑啉胺化合物 4c 具有强大和选择性的 H3R 拮抗活性（IC < 0.04 μM）。化合物 4c 对 hERG 离子通道没有任何活性，也没有泛分析干扰化合物的不良倾向。药代动力学研究表明，4c 可以穿过血脑屏障，体内研究表明，4c 可诱导肥胖小鼠厌食和体重减轻，但对瘦小鼠没有作用。这些数据表明，通过拮抗 H3R，4c 有作为抗肥胖候选药物的治疗潜力。
