Pyrazole-based cathepsin S inhibitors with arylalkynes as P1 binding elements.
A crystal structure of 1 bound to a Cys25Ser mutant of cathepsin S helped to elucidate the binding mode of a previously disclosed series of pyrazole-based CatS inhibitors and facilitated the design of a new class of arylalkyne analogs. Optimization of the alkyne and tetrahydropyridine portions of the pharmacophore provided potent CatS inhibitors (IC50=40-300 nM), and an X-ray structure of 32 revealed that the arylalkyne moiety binds in the S1 pocket of the enzyme.
Ameriks
Michael K
MK
Johnson & Johnson Pharmaceutical Research & Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA. mameriks@its.jnj.com
Axe
Frank U
FU
Bembenek
Scott D
SD
Edwards
James P
JP
Gu
Yin
Y
Karlsson
Lars
L
Randal
Mike
M
Sun
Siquan
S
Thurmond
Robin L
RL
Zhu
Jian
J
D019943:Amino Acid Substitution; D001665:Binding Sites; D002403:Cathepsins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D016297:Mutagenesis, Site-Directed; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship
D011480:Protease Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D011994:Recombinant Proteins; D002403:Cathepsins; C028217:cathepsin S