Structure-activity relationship study and drug profile of N-(4-fluorophenylsulfonyl)-L-valyl-L-leucinal (SJA6017) as a potent calpain inhibitor.
Novel N-arylsulfonyldipeptidyl aldehyde derivatives were prepared by DMSO oxidation from the corresponding dipeptide alcohol, and their potencies as calpain inhibitors were evaluated in vitro. Among them, N-(4-fluorophenylsulfonyl)-l-valyl-l-leucinal (8, SJA6017) potently inhibited calpains. 8 also inhibited cathepsin B and L but did not inhibit other cysteine proteases (interleukin 1beta-converting enzyme), serine proteases (trypsin, chymotrypsin, thrombin, factor VIIa, factor Xa), or proteasome. Preliminary cytotoxicity studies of 8 exhibited a relatively safe profile.
Inoue
Jun
J
Kobe Creative Center, Senju Pharmaceutical Co., LTD, 1-5-4 Murotani, Nishi-ku, Kobe, Hyogo 651-2241, Japan. jun-inoue@senju.co.jp
Nakamura
Masayuki
M
Cui
Ying-She
YS
Sakai
Yusuke
Y
Sakai
Osamu
O
Hill
Jeanette R
JR
Wang
Kevin K W
KK
Yuen
Po-Wai
PW
D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D018938:Caco-2 Cells; D002154:Calpain / Q000037:antagonists & inhibitors*; D002478:Cells, Cultured; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D004151:Dipeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004285:Dogs; D000882:Haplorhini; D022781:Hepatocytes / Q000201:enzymology; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008861:Microsomes / Q000378:metabolism; D010539:Permeability; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D051381:Rats; D013045:Species Specificity; D013329:Structure-Activity Relationship; D023382:Toxicity Tests, Acute; D036401:Toxicity Tests, Chronic
D001798:Blood Proteins; D004151:Dipeptides; C109145:N-(4-fluorophenylsulfonyl)-L-valyl-L-leucinal; D011480:Protease Inhibitors; D003577:Cytochrome P-450 Enzyme System; D002154:Calpain