Defining desirable central nervous system drug space through the alignment of molecular properties, in vitro ADME, and safety attributes.
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.
558 Eastern Point Road, Groton, CT, USA. travis.t.wager@pfizer.com
Travis T
TT
Wager
Ramalakshmi Y
RY
Chandrasekaran
Xinjun
X
Hou
Matthew D
MD
Troutman
Patrick R
PR
Verhoest
Anabella
A
Villalobos
Yvonne
Y
Will
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002490:Central Nervous System / Q000187:drug effects*; D002491:Central Nervous System Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D004285:Dogs; D015195:Drug Design; D004847:Epithelial Cells / Q000187:drug effects; D006801:Humans; D012449:Safety; D012995:Solubility
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002491:Central Nervous System Agents