Structure−Activity Relationships of Boronic Acid Inhibitors of Dipeptidyl Peptidase IV. 1. Variation of the P2 Position of Xaa-boroPro Dipeptides

• Published in: Journal of medicinal chemistry 1996-05, Vol.39 (10), p.2087-2094
• Main Authors: Coutts, Simon J, Kelly, Terence A, Snow, Roger J, Kennedy, Charles A, Barton, Randall W, Adams, Julian, Krolikowski, Dale A, Freeman, Dorothy M, Campbell, Scot J, Ksiazek, John F, Bachovchin, William W
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Boronic Acids - chemistry; Boronic Acids - pharmacology; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases - antagonists & inhibitors; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Humans; Immunomodulators; Lymphocyte Culture Test, Mixed; Magnetic Resonance Spectroscopy; Mass Spectrometry; Medical sciences; Pharmacology. Drug treatments; Stereoisomerism; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm950732f

A series of prolineboronic acid (boroPro) containing dipeptides were synthesized and assayed for their ability to inhibit the serine protease dipeptidyl peptidase IV (DPPIV). Inhibitory activity, which requires the (R)-stereoisomer of boroPro in the P1 position, appears to tolerate a variety of l-amino acids in the P2 position. Substitution at the P2 position which is not tolerated include the d-amino acids, α,α-disubstituted amino acids, and glycine. Specificity against DPPII and proline specific endopeptidase is reported. A correlation between the ability to inhibit DPPIV in cell culture and in the human mixed lymphocyte reaction is demonstrated. A synthesis of prolineboronic acid is reported as well as conditions for generating the fully unprotected boronic acid dipeptides in either their cyclic or acyclic forms.