Aminomethylpyrimidines as novel DPP-IV inhibitors: a 10(5)-fold activity increase by optimization of aromatic substituents.
The influence of aromatic substitution on a newly discovered class of inhibitors of dipeptidyl peptidase IV was investigated. A 10(5)-fold increase in potency was achieved by the optimization of aromatic substituents in a parallel chemistry program. The observed SAR could be explained by an X-ray structure of the protein-ligand complex.
Pharma Division, Preclinical Research, F. Hoffmann-La Roche Ltd, CH-4070 Basel, Switzerland. jens-uwe.peters@roche.com
Jens-Uwe
JU
Peters
Silja
S
Weber
Stéphane
S
Kritter
Peter
P
Weiss
Angelina
A
Wallier
Markus
M
Boehringer
Michael
M
Hennig
Bernd
B
Kuhn
Bernd-Michael
BM
Loeffler
D000243:Adenosine Deaminase / Q000378:metabolism; D058892:Adenosine Deaminase Inhibitors; D006023:Glycoproteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011480:Protease Inhibitors / Q000737:chemistry* / Q000378:metabolism; D011743:Pyrimidines / Q000737:chemistry* / Q000378:metabolism
D058892:Adenosine Deaminase Inhibitors; D006023:Glycoproteins; D011480:Protease Inhibitors; D011743:Pyrimidines; D000243:Adenosine Deaminase