title: A multi-endpoint matched molecular pair (MMP) analysis of 6-membered heterocycles.
abstract: Aromatic rings, ubiquitous in pharmaceutical compounds, are often exchanged with another ring during the optimization process of drug discovery. Inevitably, the preferred ring system for one endpoint may prove detrimental to another, thus necessitating a holistic, multiple endpoint optimization approach for finding the ideal replacement. Accordingly, we conducted an extensive matched molecular pair (MMP) analysis of common 6-membered aromatic rings across 4 endpoints critical for drug discovery (logD lipophilicity, microsomal metabolism, P-gp efflux and passive permeability). We also investigated the effect of context by considering the connecting atom. Heat maps were created as a simple yet comprehensive way to view and analyze the vast amount of interrelated data. Paired difference statistical tests were used to identify transforms with changes that were significantly different from zero. We conclude that the heat maps of transforms provide a unique and powerful approach for multiparameter optimization.
authors.affiliation: Computational ADME Group, Department of Pharmacokinetics, Dynamics, and Metabolism, Pfizer Worldwide Research & Development, Groton, CT 06340, USA. Electronic address: george.c.chang@pfizer.com.
authors.forename: George
authors.initials: G
authors.lastname: Chang
authors.affiliation: Pfizer Worldwide Research and Development, Cardiovascular and Metabolic Disease Medicinal Chemistry and Research Unit, 610 Main Street, Cambridge, MA 02139, USA.
authors.forename: Kim
authors.initials: K
authors.lastname: Huard
authors.affiliation: Computational ADME Group, Department of Pharmacokinetics, Dynamics, and Metabolism, Pfizer Worldwide Research & Development, Groton, CT 06340, USA.
authors.forename: Gregory W
authors.initials: GW
authors.lastname: Kauffman
authors.affiliation: Pfizer Worldwide Research and Development, Neuroscience Medicinal Chemistry and Neuroscience Research Unit, 610 Main Street, Cambridge, MA 02139, USA.
authors.forename: Antonia F
authors.initials: AF
authors.lastname: Stepan
authors.affiliation: Computational ADME Group, Department of Pharmacokinetics, Dynamics, and Metabolism, Pfizer Worldwide Research & Development, Groton, CT 06340, USA.
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Keefer
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D002463:Cell Membrane Permeability; D004285:Dogs; D055808:Drug Discovery / Q000379:methods*; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D061985:Madin Darby Canine Kidney Cells; D008862:Microsomes, Liver / Q000378:metabolism
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D006573:Heterocyclic Compounds, 1-Ring
keywords: Human liver microsomal metabolism; LogD lipophilicity; Matched molecular pair; Multiparameter optimization; P-gp efflux; Passive membrane permeability