title: Acidic and basic drugs in medicinal chemistry: a perspective.
abstract: The acid/base properties of a molecule are among the most fundamental for drug action. However, they are often overlooked in a prospective design manner unless it has been established that a certain ionization state (e.g., quaternary base or presence of a carboxylic acid) appears to be required for activity. In medicinal chemistry optimization programs it is relatively common to attenuate basicity to circumvent undesired effects such as lack of biological selectivity or safety risks such as hERG or phospholipidosis. However, teams may not prospectively explore a range of carefully chosen compound pKa values as part of an overall chemistry strategy or design hypothesis. This review summarizes the potential advantages and disadvantages of both acidic and basic drugs and provides some new analyses based on recently available public data.
authors.affiliation: Vertex Pharmaceuticals Incorporated , 50 Northern Avenue Boston, Massachusetts 02210, United States.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Charifson
authors.forename: W Patrick
authors.initials: WP
authors.lastname: Walters
mesh_terms: D001682:Biological Availability; D062126:Databases, Chemical; D004333:Drug Administration Routes; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007477:Ions; D007668:Kidney / Q000378:metabolism; D058116:Lewis Acids / Q000737:chemistry*; D058115:Lewis Bases / Q000737:chemistry*; D008099:Liver / Q000378:metabolism; D010539:Permeability; D004364:Pharmaceutical Preparations / Q000737:chemistry* / Q000378:metabolism; D010599:Pharmacokinetics; D011485:Protein Binding; D012995:Solubility; D014018:Tissue Distribution
chemical_list: D007477:Ions; D058116:Lewis Acids; D058115:Lewis Bases; D004364:Pharmaceutical Preparations