期刊
ACS CHEMICAL NEUROSCIENCE
卷 7, 期 6, 页码 767-775出版社
AMER CHEMICAL SOC
DOI: 10.1021/acschemneuro.6b00029
关键词
Attrition; central nervous system (CNS); CNS candidates; CNS drugs; CNS drug design; CNS MPO; desirability score; efficacious drug concentration (C-eff); Harrington optimization; human liver microsome stability; hydrogen-bond donor; lipophilicity; Madin-Darby canine kidney; molecular weight; most basic pK(a); multiparameter optimization (MPO); multivariant optimization; passive permeability; P-glycoprotein (P-gp); polarity; topological polar surface area; unbound intrinsic clearance
Significant progress has been made in prospectively designing molecules using the central nervous system multiparameter optimization (CNS MPO) desirability tool, as evidenced by the analysis reported herein of a second wave of drug candidates that originated after the development and implementation of this tool. This simple-to-use design algorithm has expanded design space for CNS candidates and has further demonstrated the advantages of utilizing a flexible, multiparameter approach in drug discovery rather than individual parameters and hard cutoffs of physicochemical properties. The CNS MPO tool has helped to increase the percentage of compounds nominated for clinical development that exhibit alignment of ADME attributes, cross the blood brain barrier, and reside in lower-risk safety space (low ClogP and high TPSA). The use of this tool has played a role in reducing the number of compounds submitted to exploratory toxicity studies and increasing the survival of our drug candidates through regulatory toxicology into First in Human studies. Overall, the CNS MPO algorithm has helped to improve the prioritization of design ideas and the quality of the compounds nominated for clinical development.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据