Identification of a novel class of succinyl-nitrile-based Cathepsin S inhibitors

Younes Bekkali; David S Thomson; Raj Betageri; Michel J Emmanuel; Ming-Hong Hao; Eugene Hickey; Weimin Liu; Usha Patel; Yancey D Ward; Erick R R Young; Richard Nelson; Alison Kukulka; Maryanne L Brown; Kathy Crane; Della White; Dorothy M Freeman; Mark E Labadia; Jessi Wildeson; Denice M Spero

doi:10.1016/j.bmcl.2007.02.046

Identification of a novel class of succinyl-nitrile-based Cathepsin S inhibitors

Bioorg Med Chem Lett. 2007 May 1;17(9):2465-9. doi: 10.1016/j.bmcl.2007.02.046. Epub 2007 Feb 23.

Affiliation

¹ Department of Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877-0368, USA. [email protected]

PMID: 17379516
DOI: 10.1016/j.bmcl.2007.02.046

Abstract

The synthesis and in vitro activities of a series of succinyl-nitrile-based inhibitors of Cathepsin S are described. Several members of this class show nanomolar inhibition of the target enzyme as well as cellular potency. The inhibitors displaying the greatest potency contain N-alkyl substituted piperidine and pyrrolidine rings spiro-fused to the alpha-carbon of the P1 residue.

MeSH terms

Catalytic Domain
Cathepsins / antagonists & inhibitors*
Chemistry, Pharmaceutical / methods*
Dipeptides / chemistry
Drug Design
Humans
Models, Chemical
Molecular Conformation
Nitriles / chemistry*
Nitriles / classification
Peptides / chemistry
Piperidines / chemistry
Pyrrolidines / chemistry
Structure-Activity Relationship

Substances

Dipeptides
Nitriles
Peptides
Piperidines
Pyrrolidines
piperidine
Cathepsins
cathepsin S
pyrrolidine