A multi-endpoint matched molecular pair (MMP) analysis of 6-membered heterocycles. Issue 1 (1st January 2017)

• Record Type: Journal Article
• Authors: Chang, George; Huard, Kim; Kauffman, Gregory W.; Stepan, Antonia F.; Keefer, Christopher E.
• Is Part Of: Bioorganic & medicinal chemistry. Volume 25:Issue 1(2017)
• Page Start: 381
• Page End: 388
• Publication Date: 2017-01-01
• Subjects: Matched molecular pair -- Multiparameter optimization -- Log D lipophilicity -- Human liver microsomal metabolism -- P-gp efflux -- Passive membrane permeability; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2016.11.004
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: 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 (log D 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.