Synthesis and Characterization of Constrained Peptidomimetic Dipeptidyl Peptidase IV Inhibitors:  Amino-Lactam boroAlanines

• Published in: Journal of medicinal chemistry 2007-05, Vol.50 (10), p.2391-2398
• Main Authors: Lai, Jack H, Wu, Wengen, Zhou, Yuhong, Maw, Hlaing H, Liu, Yuxin, Milo, Lawrence J, Poplawski, Sarah E, Henry, Gillian D, Sudmeier, James L, Sanford, David G, Bachovchin, William W
• Format: Article
• Language: English
• Subjects: Alanine - analogs & derivatives; Alanine - chemical synthesis; Alanine - chemistry; Biological and medical sciences; Biomimetics; Boric Acids - chemical synthesis; Boric Acids - chemistry; Boronic Acids - chemical synthesis; Boronic Acids - chemistry; Dipeptidyl Peptidase 4 - chemistry; Dipeptidyl-Peptidase IV Inhibitors; General and cellular metabolism. Vitamins; Humans; Hydrogen-Ion Concentration; Lactams - chemical synthesis; Lactams - chemistry; Medical sciences; Models, Molecular; Peptides - chemistry; Pharmacology. Drug treatments; Pyrrolidinones - chemical synthesis; Pyrrolidinones - chemistry; Stereoisomerism; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm061321+

We describe here the epimerization-free synthesis and characterization of a new class of conformationally constrained lactam aminoboronic acid inhibitors of dipeptidyl peptidase IV (DPP IV; E.C. 3.4.14.5). These compounds have the advantage that they cannot undergo the pH-dependent cyclization prevalent in most dipeptidyl boronic acids that attenuates their potency at physiological pH. For example, d-3-amino-1-[l-1-boronic-ethyl]-pyrrolidine-2-one (amino-d-lactam-l-boroAla), one of the best lactam inhibitors of DPP IV, is several orders of magnitude less potent than l-Ala-l-boroPro, as measured by K i values (2.3 nM vs 30 pM, respectively). At physiological pH, however, it is actually more potent than l-Ala-l-boroPro, as measured by IC50 values (4.2 nM vs 1400 nM), owing to the absence of the potency-attenuating cyclization. In an interesting and at first sight surprising reversal of the relationship between stereochemistry and potency observed with the conformationally unrestrained Xaa-boroPro class of inhibitors, the l−l diastereomers of the lactams are orders of magnitude less effective than the d−l lactams. However, this interesting reversal and the unexpected potency of the d−l lactams as DPP IV inhibitors can be understood in structural terms, which is explained and discussed here.