Structural Aspects of Proline Methanologues in Drug Design, Optimization, and Development

The primary objective of this Perspective is to highlight the potential merits of replacing a proline moiety in a drug design enterprise with a surrogate consisting of a proline that incorporates a bridged methano ring, designated as a methanologue. Emphasis is placed on the effect of the methano bridge on the conformational properties of the embedded proline within a drug molecule, and how this influences the associated geometric parameters and stereoelectronic features of the corresponding amides, which can lead to an enhancement of biological activity and metabolic stability. Thus, the 3-dimensional structures of different categories of proline methanologues delineating precisely annotated angular and interatomic distances extracted from crystallographic data are analyzed and discussed against the backdrop of their inclusion as preferred pharmacophoric elements in drug molecules. The <i>in vitro</i> and <i>in vivo</i> activities of investigational and marketed drug molecules engineered to include methylene-bridged proline units are discussed for a variety of biological targets designed to address a range of diseases related to specific human pathologies.