Structure-activity relationships of boronic acid inhibitors of dipeptidyl peptidase IV. 1. Variation of the P2 position of Xaa-boroPro dipeptides.

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Coutts SJ, Kelly TA, Snow RJ, Kennedy CA, Barton RW, Adams J, Krolikowski DA, Freeman DM, Campbell SJ, Ksiazek JF, Bachovchin WW

Structure-activity relationships of boronic acid inhibitors of dipeptidyl peptidase IV. 1. Variation of the P2 position of Xaa-boroPro dipeptides.

J Med Chem. 1996 May 10;39(10):2087-94.

PubMed ID

8642568 [ View in PubMed

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Abstract

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, alpha,alpha-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.

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Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
(2R)-N-[(2R)-2-(DIHYDROXYBORYL)-1-L-PROLYLPYRROLIDIN-2-YL]-N-[(5R)-5-(DIHYDROXYBORYL)-1-L-PROLYLPYRROLIDIN-2-YL]-L-PROLINAMIDE	Dipeptidyl peptidase 4	IC 50 (nM)	20	N/A	N/A	Details