Discovery, Structure−Activity Relationship, and Pharmacological Evaluation of (5-Substituted-pyrrolidinyl-2-carbonyl)-2-cyanopyrrolidines as Potent Dipeptidyl Peptidase IV Inhibitors

Abstract

A series of (5-substituted pyrrolidinyl-2-carbonyl)-2-cyanopyrrolidine (C5-Pro-Pro) analogues was discovered as dipeptidyl peptidase IV (DPPIV) inhibitors as a potential treatment of diabetes and obesity. X-ray crystallography data show that these inhibitors bind to the catalytic site of DPPIV with the cyano group forming a covalent bond with the serine residue of DPPIV. The C5-substituents make various interactions with the enzyme and affect potency, chemical stability, selectivity, and PK properties of the inhibitors. Optimized analogues are extremely potent with subnanomolar K(i)'s, are chemically stable, show very little potency decrease in the presence of plasma, and exhibit more than 1,000-fold selectivity against related peptidases. The best compounds also possess good PK and are efficacious in lowering blood glucose in an oral glucose tolerance test in ZDF rats.

Mutant cycle analysis with modified saxitoxins reveals specific interactions critical to attaining high-affinity inhibition of hNa V 1.7

“…It is possible, however, that STX and STX analogs adopt more than one high-affinity binding arrangement within the mouth of the channel. In native rNa V 1.4, the canonical STX binding model may indeed be preferred, but in certain mutant Na V s or with specific STX derivatives the docking orientation suggested by our findings could be favored (42)(43)(44). The potential of bis-guanidinium toxins to occlude site 1 through disparate binding modes presents an unusual challenge for engineering subtype-selective inhibitors of Na V function around this chemotype.…”

Inhibition of dipeptidyl peptidase IV (DPP IV) is one of the mechanisms explaining the hypoglycemic effect of berberine

“…The 3D coordinates of DPP IV were retrieved from the Protein Data Bank (PDB code: 2G63) [49]. The selected structure is of the best 3D resolution (2.0 Å) compared to other available DPP IV structures.…”

“…The compound was docked into the binding site of DPP IV (PDB code: 2G63, resolution = 2.0 Å) [49] employing FRED software [46]. This docking engine takes a multiconformer database of one or more ligands, a target protein structure, a box defining the active site of the protein based on the cocrystallized ligand and several optional parameters as input.…”

“…The conformational space of berberine was explored using OMEGA software. The best docking conditions utilized were those succeeded to retrieve the pose of the co-crystallized ligand (cyanopyrrolidine inhibitor 24b [49], fig. 3).…”

Design, Synthesis, and Pharmacological Evaluation of Fused β-Homophenylalanine Derivatives as Potent DPP-4 Inhibitors

“…2 Secreted from the L cells of the small intestine, 3 GLP-1 stimulates glucose-induced insulin secretion, inhibits glucagon secretion, 4 and delays the gastric emptying, all of which are beneficial in controlling the blood glucose. 5 GLP-1 is one of the substrates of dipeptidyl peptidase-4 (DPP-4, also known as CD26). 3 By cleaving a dipeptide from the N terminus, DPP-4 efficiently inactivates the active form of GLP-1.…”