title: Central Nervous System Multiparameter Optimization Desirability: Application in Drug Discovery.
abstract: 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.
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Worldwide Research and Development , 610 Main Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Travis T
authors.initials: TT
authors.lastname: Wager
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Worldwide Research and Development , 610 Main Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Xinjun
authors.initials: X
authors.lastname: Hou
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Worldwide Research and Development , 610 Main Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Patrick R
authors.initials: PR
authors.lastname: Verhoest
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Worldwide Research and Development , 610 Main Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Anabella
authors.initials: A
authors.lastname: Villalobos
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000465:Algorithms; D000818:Animals; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D002490:Central Nervous System / Q000187:drug effects* / Q000378:metabolism*; D015195:Drug Design; D006801:Humans; D010539:Permeability / Q000187:drug effects
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1
keywords: Attrition; CNS MPO; CNS candidates; CNS drug design; CNS drugs; Harrington optimization; Madin−Darby canine kidney; P-glycoprotein (P-gp); central nervous system (CNS); desirability score; efficacious drug concentration (Ceff); human liver microsome stability; hydrogen-bond donor; lipophilicity; molecular weight; most basic pKa; multiparameter optimization (MPO); multivariant optimization; passive permeability; polarity; topological polar surface area; unbound intrinsic clearance