title: Solid-phase synthesis of a combinatorial array of 1,3-bis(acylamino)-2-butanones, inhibitors of the cysteine proteases cathepsins K and L.
abstract: To more rapidly prepare members of the 1,3-bis(acylamino)-2-butanone class of cysteine protease inhibitors, a solid-phase synthesis was developed. 1-Azido-3-amino-2,2-dimethoxybutane (4), which has the two amino groups differentiated and the ketone protected as a a ketal, served as a surrogate for the 1,3-diamino-2-butanone core. Amine (4) was coupled to the BAL-resin-linked carboxylic acids derived from alpha-amino acid esters. Evaluation of a small combinatorial array by measuring inhibition constants (Ki,appS) against cathepsins K, L, and B provided some structure-activity relationship trends with respect to selectivity and potency. Novel, potent inhibitors of cathepsins K and L were identified.
authors.affiliation: Department of Medicinal Chemistry, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406, USA.
authors.forename: D S
authors.initials: DS
authors.lastname: Yamashita
authors.forename: X
authors.initials: X
authors.lastname: Dong
authors.forename: H J
authors.initials: HJ
authors.lastname: Oh
authors.forename: C S
authors.initials: CS
authors.lastname: Brook
authors.forename: T A
authors.initials: TA
authors.lastname: Tomaszek
authors.forename: L
authors.initials: L
authors.lastname: Szewczuk
authors.forename: D G
authors.initials: DG
authors.lastname: Tew
authors.forename: D F
authors.initials: DF
authors.lastname: Veber
mesh_terms: D002074:Butanones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D056657:Cathepsin K; D056668:Cathepsin L; D002403:Cathepsins / Q000037:antagonists & inhibitors*; D020650:Combinatorial Chemistry Techniques / Q000379:methods*; D003546:Cysteine Endopeptidases; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D010450:Endopeptidases; D007700:Kinetics; D008958:Models, Molecular; D013329:Structure-Activity Relationship
chemical_list: C406673:1,3-bis(acylamino)-2-butanone; D002074:Butanones; D015853:Cysteine Proteinase Inhibitors; D002403:Cathepsins; D010450:Endopeptidases; D003546:Cysteine Endopeptidases; D056668:Cathepsin L; D056657:Cathepsin K