Synthesis of peptide aldehyde derivatives as selective inhibitors of human cathepsin L and their inhibitory effect on bone resorption.
Cathepsin L, a lysosomal cysteine protease, is secreted by osteoclasts and participates in bone collagen degradation. In a search for cathepsin L inhibitors as antiosteoporotic agents, a series of peptide aldehyde derivatives were prepared by two synthetic approaches, DMSO oxidation of the corresponding alcohol derivatives and DIBAL-H reduction of the corresponding N, O-dimethylhydroxylamide derivatives, and evaluated for inhibitory activity against human cathepsin L and for inhibitory effects on bone resorption. Some of the peptide aldehyde derivatives including alpha-acylamino aldehyde derivatives showed potent activities. Among these compounds, N-(1-naphthalenylsulfonyl-L-isoleucyl-L-tryptophanal (12) was selected as a candidate for further investigation. Compound 12, a potent, selective, and reversible inhibitor of human cathepsin L with an IC50 of 1.9 nM, inhibited the release of Ca2+ and hydroxyproline from bone in in vitro bone culture system and also prevented bone loss in ovariectomized mice at an oral dose of 50 mg/kg.
Yasuma
T
T
Pharmaceutical Research Division and Discovery Research Division, Takeda Chemical Industries, Ltd., 17-85, Jusohonmachi 2-Chome, Yodogawa-ku, Osaka 532-8686, Japan. YASUMA_TSUNEO@takeda.co.jp
Oi
S
S
Choh
N
N
Nomura
T
T
Furuyama
N
N
Nishimura
A
A
Fujisawa
Y
Y
Sohda
T
T
D000447:Aldehydes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001862:Bone Resorption / Q000188:drug therapy*; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D056668:Cathepsin L; D002403:Cathepsins / Q000037:antagonists & inhibitors*; D003546:Cysteine Endopeptidases; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004151:Dipeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010450:Endopeptidases; D005260:Female; D006801:Humans; D006909:Hydroxyproline / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D009282:Naphthalenesulfonates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009924:Organ Culture Techniques; D010052:Ovariectomy; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D012886:Skull / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship
D000447:Aldehydes; D015853:Cysteine Proteinase Inhibitors; D004151:Dipeptides; C115425:N-(1-naphthalenylsulfonyl)isoleucyl-tryptophanal; D009282:Naphthalenesulfonates; D010455:Peptides; D011994:Recombinant Proteins; D002403:Cathepsins; D010450:Endopeptidases; D003546:Cysteine Endopeptidases; C534281:CTSL protein, human; D056668:Cathepsin L; C534278:Ctsl protein, mouse; C534280:Ctsl protein, rat; D006909:Hydroxyproline; D002118:Calcium