ABSTRACT
A series of seco-prolinenitrile-containing dipeptides were synthesized and assayed as inhibitors of the N-terminal sequence-specific serine protease dipeptidyl peptidase IV, a promising new target for treatment of type 2 diabetes. The inhibitors described herein assess the minimum structural requirements at P1 for this enzyme, resulting in the identification of inhibitors with low nM potency.
Subject(s)
Adenosine Deaminase/chemistry , Dipeptides , Dipeptidyl Peptidase 4/chemistry , Enzyme Inhibitors , Glycoproteins/chemistry , Nitriles , Proline/chemistry , Aniline Compounds/metabolism , Dipeptides/chemical synthesis , Dipeptides/chemistry , Dipeptides/pharmacology , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Humans , Nitriles/chemical synthesis , Nitriles/chemistry , Nitriles/pharmacologyABSTRACT
Dipeptidyl peptidase IV (DPP4) is a multifunctional type II transmembrane serine peptidase which regulates various physiological processes, most notably plasma glucose homeostasis by cleaving peptide hormones glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide. Inhibition of DPP4 is a potentially valuable therapy for type 2 diabetes. Synthesis and structure-activity relationships of a series of substituted diprolyl nitriles are described, leading to the identification of compound 1 with a measured DPP4 K(i) of 3.6 nM.
Subject(s)
Dipeptidyl Peptidase 4/metabolism , Nitriles/pharmacology , Protease Inhibitors/pharmacology , Binding Sites , Cyclization , Dipeptidyl Peptidase 4/chemistry , Models, Molecular , Molecular Structure , Nitriles/chemistry , Protease Inhibitors/chemistry , Protein Structure, TertiaryABSTRACT
A series of methanoprolinenitrile-containing dipeptide mimetics were synthesized and assayed as inhibitors of the N-terminal sequence-specific serine protease dipeptidyl peptidase IV (DPP-IV). The catalytic action of DPP-IV is the principle means of degradation of glucagon-like peptide-1, a key mediator of glucose-stimulated insulin secretion, and DPP-IV inhibition shows clinical benefit as a novel mechanism for treatment of type 2 diabetes. However, many of the reversible inhibitors to date suffer from chemical instability stemming from an amine to nitrile intramolecular cyclization. Installation of a cyclopropyl moiety at either the 3,4- or 4,5-position of traditional 2-cyanopyrrolidide proline mimetics led to compounds with potent inhibitory activity against the enzyme. Additionally, cis-4,5-methanoprolinenitriles with beta-branching in the N-terminal amino acid provided enhanced chemical stability and high inhibitory potency. This class of inhibitors also exhibited the ability to suppress prandial glucose elevations after an oral glucose challenge in male Zucker rats.
