Solid-phase synthesis of a combinatorial array of 1,3-bis(acylamino)-2-butanones, inhibitors of the cysteine proteases cathepsins K and L.
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.
Yamashita
D S
DS
Department of Medicinal Chemistry, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406, USA.
Dong
X
X
Oh
H J
HJ
Brook
C S
CS
Tomaszek
T A
TA
Szewczuk
L
L
Tew
D G
DG
Veber
D F
DF
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
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