title: Peptidomimetic 2-cyanopyrrolidines as potent selective cathepsin L inhibitors.
abstract: Cathepsins have been found to have important physiological roles. The implication of cathepsin L in various types of cancers is well established. In a search for selective cathepsin L inhibitors as anticancer agents, a series of 2-cyanoprrolidine peptidomimetics, carrying a nitrile group as warhead, were designed. Two series of compounds, one with a benzyl moiety and a second with an isobutyl moiety at P(2) position of the enzyme were synthesized. The synthesized compounds were evaluated for inhibitory activity against human cathepsin L and cathepsin B. Although, none of the compounds showed promising inhibitory activity, (E)N-{(S)1-[(S)2-cyano-1-pyrrolidinecarbonyl]-3-methylbutyl}-2,3-diphenylacrylamide (24) with an isobutyl moiety at P(2) was found to show selectivity as a cathepsin L inhibitor (Ki 5.3 microM for cathepsin L and Ki > 100 microM for cathepsin B). This compound could act as a new lead for the further development of improved inhibitors within this inhibitor type.
authors.affiliation: Pharmacy Department, Faculty of Technology and Engineering, The M S University of Baroda, Vadodara, India. mryadav11@yahoo.co.in
authors.forename: Mange R
authors.initials: MR
authors.lastname: Yadav
authors.forename: Anil K
authors.initials: AK
authors.lastname: Shinde
authors.forename: Bishram S
authors.initials: BS
authors.lastname: Chouhan
authors.forename: Rajani
authors.initials: R
authors.lastname: Giridhar
authors.forename: Robert
authors.initials: R
authors.lastname: Menard
mesh_terms: D040761:Biomimetic Materials / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D056668:Cathepsin L; D002403:Cathepsins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D003486:Cyanides / Q000737:chemistry*; D003546:Cysteine Endopeptidases / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D010455:Peptides / Q000737:chemistry*; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D003486:Cyanides; D015853:Cysteine Proteinase Inhibitors; D010455:Peptides; D011759:Pyrrolidines; D002403:Cathepsins; D003546:Cysteine Endopeptidases; C534281:CTSL protein, human; D056668:Cathepsin L