Identification of potent and selective cathepsin S inhibitors containing different central cyclic scaffolds.
Starting from the weakly active dual CatS/K inhibitor 5, structure-based design supported by X-ray analysis led to the discovery of the potent and selective (>50,000-fold vs CatK) cyclopentane derivative 22 by exploiting specific ligand-receptor interactions in the S2 pocket of CatS. Changing the central cyclopentane scaffold to the analogous pyrrolidine derivative 57 decreased the enzyme as well as the cell-based activity significantly by 24- and 69-fold, respectively. The most promising scaffold identified was the readily accessible proline derivative (e.g., 79). This compound, with an appealing ligand efficiency (LE) of 0.47, included additional structural modifications binding in the S1 and S3 pockets of CatS, leading to favorable in vitro and in vivo properties. Compound 79 reduced IL-2 production in a transgenic DO10.11 mouse model of antigen presentation in a dose-dependent manner with an ED50 of 5 mg/kg.
Discovery Chemistry, ‡Cardiovascular and Metabolic Diseases, §Discovery Technologies, ∥Drug Metabolism and Pharmacokinetics, ⊥Process Research and Synthesis, Pharma Research and Early Development (pRED), F. Hoffmann-La Roche Ltd. , Grenzacherstrasse 124, Basel CH-4070, Switzerland.
Hans
H
Hilpert
Harald
H
Mauser
Roland
R
Humm
Lilli
L
Anselm
Holger
H
Kuehne
Guido
G
Hartmann
Sabine
S
Gruener
David W
DW
Banner
Joerg
J
Benz
Bernard
B
Gsell
Andreas
A
Kuglstatter
Martine
M
Stihle
Ralf
R
Thoma
Rubén Alvarez
RA
Sanchez
Hans
H
Iding
Beat
B
Wirz
Wolfgang
W
Haap
D000818:Animals; D002403:Cathepsins / Q000037:antagonists & inhibitors*; D003517:Cyclopentanes / Q000737:chemistry; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D006801:Humans; D051379:Mice; D011392:Proline / Q000031:analogs & derivatives; D013329:Structure-Activity Relationship
D003517:Cyclopentanes; D015853:Cysteine Proteinase Inhibitors; D011392:Proline; D002403:Cathepsins; C028217:cathepsin S