title: Peptidic 1-cyanopyrrolidines: synthesis and SAR of a series of potent, selective cathepsin inhibitors.
abstract: 1-Cyanopyrrolidines have previously been reported to inhibit cysteinyl cathepsins (Falgueyret, J.-P. et al., J. Med. Chem. 2001, 44, 94). In order to optimize binding interactions for a given cathepsin and simultaneously reduce interactions with the other closely related enzymes, small peptidic substituents were introduced to the 1-cyanopyrrolidine scaffold, either at the 2-position starting with proline or at the 3-position of aminopyrrolidines. The resulting novel compounds proved to be micromolar inhibitors of cathepsin B (Cat B) but nanomolar to picomolar inhibitors of cathepsins K, L, and S (Cat K, Cat L, Cat S). Several of the compounds were >20-fold selective versus the other three cathepsins. SAR trends were observed, most notably the remarkable potency of Cat L inhibitors based on the 1-cyano-D-proline scaffold. The selectivity of one such compound, the 94 picomolar Cat L inhibitor 12, was demonstrated at higher concentrations in DLD-1 cells. Although none of the compounds in the proline series that was tested proved to be submicromolar in the in vitro bone resorption assay, two Cat K inhibitors in the 3-substituted pyrrolidine series, 24 and 25 were relatively potent in that assay.
authors.affiliation: Department of Medicinal Chemistry, Celera, 180 Kimball Way, South San Francisco, CA 94080, USA. bob.rydzewski@celera.com
authors.forename: Robert M
authors.initials: RM
authors.lastname: Rydzewski
authors.forename: Clifford
authors.initials: C
authors.lastname: Bryant
authors.forename: Renata
authors.initials: R
authors.lastname: Oballa
authors.forename: Gregg
authors.initials: G
authors.lastname: Wesolowski
authors.forename: Sevgi B
authors.initials: SB
authors.lastname: Rodan
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Bass
authors.forename: Darren H
authors.initials: DH
authors.lastname: Wong
mesh_terms: D000818:Animals; D001862:Bone Resorption / Q000188:drug therapy; D002403:Cathepsins / Q000037:antagonists & inhibitors*; D004151:Dipeptides / Q000138:chemical synthesis* / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D051379:Mice; D009570:Nitriles / Q000138:chemical synthesis / Q000494:pharmacology; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D004151:Dipeptides; D004791:Enzyme Inhibitors; D009570:Nitriles; D011759:Pyrrolidines; D002403:Cathepsins