title: Structure-based development of pyridoxal propionate derivatives as specific inhibitors of cathepsin K in vitro and in vivo.
abstract: We found that pyridoxal phosphate shows considerable inhibition of cathepsins. CLIK-071, in which the phosphate ester of position 3 of pyridoxal phosphate was replaced by propionate, strongly inhibited cathepsin B. Three new types of synthetic pyridoxal propionate derivatives showing specific inhibition of cathepsin K were developed. New synthetic pyridoxal propionate derivatives, -162, -163, and -164, in which the methyl arm of position 6 of CLIK-071 was additionally modified, strongly inhibited cathepsin K and cathepsin S weakly, but other cathepsins were not inhibited. CLIK-166, in which the position 4 aldehyde of CLIK-071 is replaced by a vinyl radical and position 5 is additionally modified, showed cathepsin K-specific inhibition at 10(-5) M. Pit formation due to bone collagen degradation by cathepsin K of rat osteoclasts was specifically suppressed by administration of CLIK-164, but not by inhibitors of cathepsin L or B.
authors.affiliation: Institute for Health Sciences, Tokushima Bunri University, Tokushima, 770-8514, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Katunuma
authors.forename: A
authors.initials: A
authors.lastname: Matsui
authors.forename: T
authors.initials: T
authors.lastname: Inubushi
authors.forename: E
authors.initials: E
authors.lastname: Murata
authors.forename: H
authors.initials: H
authors.lastname: Kakegawa
authors.forename: Y
authors.initials: Y
authors.lastname: Ohba
authors.forename: D
authors.initials: D
authors.lastname: Turk
authors.forename: V
authors.initials: V
authors.lastname: Turk
authors.forename: Y
authors.initials: Y
authors.lastname: Tada
authors.forename: T
authors.initials: T
authors.lastname: Asao
mesh_terms: D000818:Animals; D001862:Bone Resorption / Q000517:prevention & control; D002401:Cathepsin B / Q000037:antagonists & inhibitors; D056657:Cathepsin K; D002403:Cathepsins / Q000037:antagonists & inhibitors*; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D010010:Osteoclasts / Q000201:enzymology; D011730:Pyridoxal / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology*; D011732:Pyridoxal Phosphate / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D015853:Cysteine Proteinase Inhibitors; D011730:Pyridoxal; D011732:Pyridoxal Phosphate; D002403:Cathepsins; D002401:Cathepsin B; D056657:Cathepsin K; C534133:Ctsk protein, rat