Development of Long-Acting Dipeptidyl Peptidase-4 Inhibitors: Structural Evolution and Long-Acting Determinants

Abstract

Considerable effort has been made to achieve less frequent dosing in the development of DPP-4 inhibitors. Enthusiasm for long-acting DPP-4 inhibitors is based on the promise that such agents with less frequent dosing regimens are associated with improved patient adherence, but the rational design of long-acting DPP-4 inhibitors remains a major challenge. In this Perspective, the development of longacting DPP-4 inhibitors is comprehensively summarized to highlight the evolution of initial lead compounds on the path toward developing long-acting DPP-4 inhibitors over nearly three decades. The determinants for long duration of action are then examined, including the nature of the target, potency, binding kinetics, crystal structures, selectivity, and preclinical and clinical pharmacokinetic and pharmacodynamic profiles. More importantly, several possible approaches for the rational design of long-acting drugs are discussed. We hope that this information will facilitate the design and development of safer and more effective long-acting DPP-4 inhibitors and other oral drugs. ■ SIGNIFICANCE• The evolution of initial lead compounds on the path toward developing long-acting DPP-4 inhibitors over nearly three decades is reviewed. • The determinants for long duration of action are examined, including the nature of the target, potency, binding kinetics, crystal structures, selectivity, and preclinical and clinical PK and PD profiles. • Possible approaches for the rational design of longacting drugs are discussed.

Copper/Chiral Phosphoric-Acid-Catalyzed Intramolecular Reductive Isocyanide-Alkene (1 + 2) Cycloaddition: Enantioselective Construction of 2-Azabicyclo[3.1.0]hexanes

“…2-Azabicyclo­[3.1.0]­hexane is a key structural motif in a number of marked drugs or drug candidates with a wide range of bioactivities (Scheme a). − The unique cyclopropano-annelated architecture could reduce the lipophilicity of the parent pyrrolines and regulate the N -centered basicity. , Retrosynthetic analysis of this azabicyclo scaffold leads to basically two strategies, monoring formation and double-ring formation. Among them, intermolecular cyclopropanation of pyrrole and indole derivatives with free carbene or carbenoids represents the most straightforward approach to this scaffold; however, it often suffers from regio- and stereoselectivity, limited substrate scope, and harsh reaction conditions. − Alternatively, forming the pyrroline ring was realized through Pd-catalyzed enantioselective C–H functionalization developed by Pedroni and Cramer and Peng et al Aza-palladation of an alkene and intramolecular C­(sp 3 )–H functionalization was developed by Yang et al and Bower et al, and gold-catalyzed cycloisomerizations of ene-ynamides and Kulinkovich cyclopropanation of ene-amides also proved efficient double-ring-forming approaches to construct the scaffold.…”