Discovery of Linagliptin for the Treatment of Type 2 Diabetes Mellitus

• Published in: Successful Drug Discovery pp. 129 - 156
• Main Authors: Eckhardt, Matthias, Klein, Thomas, Nar, Herbert, Thiemann, Sandra
• Format: Book Chapter
• Language: English
• Published: Weinheim, Germany Wiley‐VCH Verlag GmbH & Co. KGaA 23.01.2015
• Subjects: clinical pharmacology; crystal structure analysis; dipeptidyl peptidase‐4 (DPP‐4) inhibitor; high throughput screening (HTS); Linagliptin; renally impaired patients; structure‐activity relationship (SAR); type 2 diabetes mellitus (T2DM)
• ISBN: 3527336850; 9783527336852
• DOI: 10.1002/9783527678433.ch7

Linagliptin is a highly potent, selective, and long‐acting dipeptidyl peptidase‐4 (DPP‐4) inhibitor of a novel chemotype that was attained upon structural optimization of a modest DPP‐4 inhibitor discovered through high throughput screening (HTS). This chapter discusses high throughput screening (HTS) optimization; rationalization of DPP‐4 inhibition potency by crystal structure analysis and studies of binding kinetics; basic physicochemical, pharmacological, and kinetic characteristics; and some preclinical studies. The X‐ray crystal structure of compound I in complex with human DPP‐4, makes it possible to highlight the main interactions of the inhibitor within the active site of the enzyme and to rationalize the observed structure‐activity relationship (SAR). The development of linagliptin included a clinical pharmacology program encompassing several single‐ and multiple‐dose randomized studies of the absorption and disposition of linagliptin in healthy subjects and patients with type 2 diabetes mellitus (T2DM).