Defining Desirable Central Nervous System Drug Space through the Alignment of Molecular Properties, in Vitro ADME, and Safety Attributes

被引：360

作者：

Wager, Travis T. ^{[1
]}

Chandrasekaran, Ramalakshmi Y. ^{[1
]}

Hou, Xinjun ^{[1
]}

Troutman, Matthew D. ^{[2
]}

Verhoest, Patrick R. ^{[1
]}

Villalobos, Anabella ^{[1
]}

Will, Yvonne ^{[3
]}

机构：

[1] Pfizer PharmaTherapeut Res & Dev, Neurosci Med Chem, Groton, CT 06340 USA

[2] Pfizer PharmaTherapeut Res & Dev, Dept Pharmacokinet Dynam & Metab Screening CoE, Groton, CT 06340 USA

[3] Pfizer PharmaTherapeut Res & Dev, Compound Safety Predict, Groton, CT 06340 USA

来源：

ACS CHEMICAL NEUROSCIENCE | 2010年 / 1卷 / 06期

关键词：

Central nervous system (CNS); CNS drugs; CNS candidates; lipophilicity; topological polar surface area; polarity; molecular weight; hydrogen bond donor; most basic pK(a); high-throughput screening; passive permeability; Madin-Darby canine kidney; P-glycoprotein; human liver microsome stability; unbound intrinsic clearance; ligand efficiency; ligand-lipophilicity efficiency; ligand-efficiency-dependent lipophilicity; drug-drug interactions; dofetilide binding; transformed human liver epithelial cells; cellular toxicity; DISCOVERY; PROLONGATION; PREDICTION; BINDING; IMPACT;

D O I：

10.1021/cn100007x

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

As part of our effort to increase survival of drug candidates and to move our medicinal chemistry design to higher probability space for success in the Neuroscience therapeutic area, we embarked on a detailed study of the property space for a collection of central nervous system (CNS) molecules. We carried out a thorough analysis of properties for 119 marketed CNS drugs and a set of 108 Pfizer CNS candidates. In particular. we focused on understanding the relationships between physicochemical properties, in vitro ADME (absorption, distribution, metabolism, and elimination) attributes, primary pharmacology binding efficiencies, and in vitro safety data for these two sets of compounds. This scholarship provides guidance for the design of CNS molecules in a property space with increased probability of success and may lead to the identification of druglike candidates with favorable safety profiles that can successfully test hypotheses in the clinic.

引用

页码：420 / 434

页数：15