title: Effect of water solvation on the lipophilicity of isomeric pyrimidine-carboxamides.
abstract: Incorporation of nitrogen is a common medicinal chemistry tactic to reduce logD values. Neighboring group participation influences logD, so the results are isomer dependent. The logD and logP differences observed between isomeric pyrimidines 1, 2 and 3 presumably result when the carbonyl or ether lone pairs are in close proximity to a heterocyclic nitrogen lone pair, recruiting water to bridge between the electron rich atoms. Various lipophilicity calculators did not discriminate between 1 (logD=2.6) and 3 (logD=1.0), but solvation energies using Poisson-Boltzmann and 3D-RISM methods rationalize the observed differences in lipophilicity among pyrimidine carboxamide isomers.
authors.affiliation: Pfizer Global Research and Development, Department of Chemistry, La Jolla, CA, United States. Electronic address: angelica.linton@pfizer.com.
authors.forename: Maria Angelica
authors.initials: MA
authors.lastname: Linton
authors.affiliation: Pfizer Global Research and Development, Department of Chemistry, La Jolla, CA, United States.
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Burke
authors.affiliation: Pfizer Global Research and Development, Department of Chemistry, La Jolla, CA, United States.
authors.forename: Ted W
authors.initials: TW
authors.lastname: Johnson
authors.affiliation: Pfizer Global Research and Development, Department of Chemistry, La Jolla, CA, United States.
authors.forename: Sacha
authors.initials: S
authors.lastname: Ninkovic
authors.affiliation: Pfizer Global Research and Development, Department of Chemistry, La Jolla, CA, United States.
authors.forename: Ketan S
authors.initials: KS
authors.lastname: Gajiwala
authors.affiliation: Pfizer Global Research and Development, Department of Chemistry, La Jolla, CA, United States.
authors.forename: Paul
authors.initials: P
authors.lastname: Richardson
authors.affiliation: Pfizer Global Research and Development, Department of Chemistry, La Jolla, CA, United States.
authors.forename: Phuong T
authors.initials: PT
authors.lastname: Le
mesh_terms: D000577:Amides / Q000737:chemistry*; D004583:Electrons; D006863:Hydrogen-Ion Concentration; D057927:Hydrophobic and Hydrophilic Interactions; D007536:Isomerism; D008958:Models, Molecular; D009584:Nitrogen / Q000737:chemistry*; D011743:Pyrimidines / Q000737:chemistry*; D012995:Solubility; D013816:Thermodynamics; D014867:Water / Q000737:chemistry*
chemical_list: D000577:Amides; D011743:Pyrimidines; D014867:Water; D009584:Nitrogen
keywords: Isomers; Lipophilicity; Lipophilicity calculators; LogD; LogP; Pyrimidines; Water solvation