2-Cyano-pyrimidines: a new chemotype for inhibitors of the cysteine protease cathepsin K.
Starting from the purine lead structure 1, a new series of cathepsin K inhibitors based on a pyrimidine scaffold have been explored. Investigations of P3 and P2 substituents based on molecular modeling suggestions resulted in potent cathepsin K inhibitors with an improved selectivity profile over other cathepsins.
Altmann
Eva
E
Novartis Institutes of BioMedical Research, CH-4002 Basel, Switzerland.
Aichholz
Reiner
R
Betschart
Claudia
C
Buhl
Thomas
T
Green
Jonathan
J
Irie
Osamu
O
Teno
Naoki
N
Lattmann
René
R
Tintelnot-Blomley
Marina
M
Missbach
Martin
M
D000818:Animals; D001665:Binding Sites; D056657:Cathepsin K; D002403:Cathepsins / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D018360:Crystallography, X-Ray; D003546:Cysteine Endopeptidases / Q000737:chemistry*; D008958:Models, Molecular; D009570:Nitriles / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D013329:Structure-Activity Relationship
D009570:Nitriles; D011480:Protease Inhibitors; D011743:Pyrimidines; D002403:Cathepsins; D003546:Cysteine Endopeptidases; D056657:Cathepsin K; C534133:Ctsk protein, rat