Pajouhesh Hassan, Lenz George R
Department of Medicinal Chemistry, Neuromed Technologies Inc., Vancouver, British Columbia, Canada V6T 1Z4.
NeuroRx. 2005 Oct;2(4):541-53. doi: 10.1602/neurorx.2.4.541.
Fundamental physiochemical features of CNS drugs are related to their ability to penetrate the blood-brain barrier affinity and exhibit CNS activity. Factors relevant to the success of CNS drugs are reviewed. CNS drugs show values of molecular weight, lipophilicity, and hydrogen bond donor and acceptor that in general have a smaller range than general therapeutics. Pharmacokinetic properties can be manipulated by the medicinal chemist to a significant extent. The solubility, permeability, metabolic stability, protein binding, and human ether-ago-go-related gene inhibition of CNS compounds need to be optimized simultaneously with potency, selectivity, and other biological parameters. The balance between optimizing the physiochemical and pharmacokinetic properties to make the best compromises in properties is critical for designing new drugs likely to penetrate the blood brain barrier and affect relevant biological systems. This review is intended as a guide to designing CNS therapeutic agents with better drug-like properties.
中枢神经系统药物的基本物理化学特性与其穿透血脑屏障的能力、亲和力及表现出的中枢神经系统活性相关。本文综述了与中枢神经系统药物成功相关的因素。中枢神经系统药物的分子量、亲脂性以及氢键供体和受体的值,总体上比一般治疗药物的范围更小。药物化学家在很大程度上可以操控药代动力学性质。中枢神经系统化合物的溶解度、渗透性、代谢稳定性、蛋白结合以及对人醚 - 去极化相关基因的抑制作用,需要与效力、选择性和其他生物学参数同时进行优化。在优化物理化学和药代动力学性质之间取得平衡,以便在性质上做出最佳折衷,对于设计可能穿透血脑屏障并影响相关生物系统的新药至关重要。本综述旨在作为设计具有更好类药性质的中枢神经系统治疗药物的指南。