Mechanisms of action of the dipeptidyl peptidase-4 inhibitor vildagliptin in humans.

Inhibition of dipeptidyl peptidase-4 (DPP-4) by vildagliptin prevents degradation of glucagon-like peptide-1 (GLP-1) and reduces glycaemia in patients with type 2 diabetes mellitus, with low risk for hypoglycaemia and no weight gain. Vildagliptin binds covalently to the catalytic site of DPP-4, eliciting prolonged enzyme inhibition. This raises intact GLP-1 levels, both after meal ingestion and in the fasting state. Vildagliptin has been shown to stimulate insulin secretion and inhibit glucagon secretion in a glucose-dependent manner. At hypoglycaemic levels, the counterregulatory glucagon response is enhanced relative to baseline by vildagliptin. Vildagliptin also inhibits hepatic glucose production, mainly through changes in islet hormone secretion, and improves insulin sensitivity, as determined with a variety of methods. These effects underlie the improved glycaemia with low risk for hypoglycaemia. Vildagliptin also suppresses postprandial triglyceride (TG)-rich lipoprotein levels after ingestion of a fat-rich meal and reduces fasting lipolysis, suggesting inhibition of fat absorption and reduced TG stores in non-fat tissues. The large body of knowledge on vildagliptin regarding enzyme binding, incretin and islet hormone secretion and glucose and lipid metabolism is summarized, with discussion of the integrated mechanisms and comparison with other DPP-4 inhibitors and GLP-1 receptor activators, where appropriate.

The individual enantiomers of cis-cromakalim possess K+ channel opening activity.

Cromakalim (BRL 34915), a racemic trans-3,4-disubstituted benzopyran, is the prototype of a novel group of vasorelaxants which act by opening K+ channels in the cell membrane, the K+ channel openers. The enantiomers of cis-cromakalim were synthesized and their biological activity compared to that of the enantiomers of (trans-)cromakalim. Both the (+)-(3R,4R) enantiomer and its (-)-(3S,4S) antipode inhibited binding of the K+ channel opener [3H]P1075 in strips of rat aorta with pKi values of 5.4 and 5.2, respectively. They relaxed noradrenaline-induced contractions of rat isolated aorta under control conditions with pD2 values of 5.7 and 5.2; their vasorelaxant potency was greatly diminished under depolarized conditions (KCl = 55 mmol/l). Both compounds increased the permeability of the cell membrane for K+ as suggested by their ability to stimulate 86Rb+ efflux from rat aortic strips. The vasorelaxant and the 86Rb+ efflux-stimulating effects of the compounds were inhibited by the sulfonylurea, glibenclamide. These results show that the enantiomers of cis-cromakalim are genuine K+ channel openers. The (R,R) enantiomer is 50 times weaker than the (-)-(3S,4R) enantiomer of cromakalim (= levcromakalim, BRL 38227) but 3 times more potent than the (+)-(3R,4S) enantiomer. These data highlight the importance of the stereochemistry at both the 3 and 4 position of the benzopyran ring.

NVP-DPP728 (1-[[[2-[(5-cyanopyridin-2-yl)amino]ethyl]amino]acetyl]-2-cyano-(S)- pyrrolidine), a slow-binding inhibitor of dipeptidyl peptidase IV.

Inhibition of dipeptidyl peptidase IV (DPP-IV) has been proposed recently as a therapeutic approach to the treatment of type 2 diabetes. N-Substituted-glycyl-2-cyanopyrrolidide compounds, typified by NVP-DPP728 (1-[[[2-[(5-cyanopyridin-2-yl)amino]ethyl]amino]acetyl]-2-cyano-(S )-p yrrolidine), inhibit degradation of glucagon-like peptide-1 (GLP-1) and thereby potentiate insulin release in response to glucose-containing meals. In the present study NVP-DPP728 was found to inhibit human DPP-IV amidolytic activity with a K(i) of 11 nM, a k(on) value of 1.3 x 10(5) M(-)(1) s(-)(1), and a k(off) of 1.3 x 10(-)(3) s(-)(1). Purified bovine kidney DPP-IV bound 1 mol/mol [(14)C]-NVP-DPP728 with high affinity (12 nM K(d)). The dissociation constant, k(off), was 1.0 x 10(-)(3) and 1.6 x 10(-)(3) s(-)(1) in the presence of 0 and 200 microM H-Gly-Pro-AMC, respectively (dissociation t(1/2) approximately 10 min). Through kinetic evaluation of DPP-IV inhibition by the D-antipode, des-cyano, and amide analogues of NVP-DPP728, it was determined that the nitrile functionality at the 2-pyrrolidine position is required, in the L-configuration, for maximal activity (K(i) of 11 nM vs K(i) values of 5.6 to >300 microM for the other analogues tested). Surprisingly, it was found that the D-antipode, despite being approximately 500-fold less potent than NVP-DPP728, displayed identical dissociation kinetics (k(off) of 1.5 x 10(-)(3) s(-)(1)). NVP-DPP728 inhibited DPP-IV in a manner consistent with a two-step inhibition mechanism. Taken together, these data suggest that NVP-DPP728 inhibits DPP-IV through formation of a novel, reversible, nitrile-dependent complex with transition state characteristics.