Pyrazole-based arylalkyne cathepsin S inhibitors. Part II: optimization of cellular potency.
Basic lipophilic substituents dramatically improved the cellular potency of a previously disclosed series of pyrazole-based arylalkyne cathepsin S inhibitors. The incorporation of substituted benzylamines in the para position of the arylalkyne maintained enzymatic activity (hCatS IC50=80-420 nM) and imparted cellular potency (IC50=0.8-4.0 microM). Further refinement of the morpholine portion of the pharmacophore enabled the identification of bicyclic piperidines with enhanced affinity for CatS (IC50=10-30 nM) and sub-micromolar cellular potency (JY Ii IC50=200-720 nM).
Ameriks
Michael K
MK
Johnson & Johnson Pharmaceutical Research and Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA. mameriks@its.jnj.com
Cai
Hui
H
Edwards
James P
JP
Gebauer
Damara
D
Gleason
Elizabeth
E
Gu
Yin
Y
Karlsson
Lars
L
Nguyen
Steven
S
Sun
Siquan
S
Thurmond
Robin L
RL
Zhu
Jian
J
D000818:Animals; D002403:Cathepsins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002460:Cell Line; D015195:Drug Design; D006801:Humans; D051379:Mice; D010880:Piperidines / Q000737:chemistry; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D010880:Piperidines; D011480:Protease Inhibitors; D011720:Pyrazoles; D002403:Cathepsins; C028217:cathepsin S