Synthesis and biological evaluation of N-mercaptoacylproline and N-mercaptoacylthiazolidine-4-carboxylic acid derivatives as leukotriene A4 hydrolase inhibitors.
We studied the synthetic modification of structurally similar N-mercaptoacyl-L-proline and (4R)-N-mercaptoacylthiazolidine-4-carboxylic acid to obtain potent leukotriene A(4) (LTA(4)) hydrolase inhibitors. An N-mercaptoacyl group, (2S)-3-mercapto-2-methylpropionyl group, was effective for both scaffolds. Additional introduction of a large substituent such as 4-isopropylbenzylthio (3f), 4-tert-butylbenzylthio (3l) or 4-cyclohexylbenzylthio group (3m) with (S)-configuration at the C(4) position of proline yielded much more potent LTA(4) hydrolase inhibitors (IC(50); 52, 31, and 34 nM, respectively) than captopril (IC(50); 630,000 nM).
Enomoto
Hiroshi
H
Nara Research & Development Center, Santen Pharmaceutical Co., Ltd, 8916-16, Takayama-cho, Ikoma-shi, Nara 630-0101, Japan. hiroshi.enomoto@santen.co.jp
Morikawa
Yuko
Y
Miyake
Yurika
Y
Tsuji
Fumio
F
Mizuchi
Maki
M
Suhara
Hiroshi
H
Fujimura
Ken-ichi
K
Horiuchi
Masato
M
Ban
Masakazu
M
D000818:Animals; D002264:Carboxylic Acids / Q000138:chemical synthesis* / Q000737:chemistry; D002626:Chemistry, Pharmaceutical / Q000379:methods; D018360:Crystallography, X-Ray / Q000379:methods; D015195:Drug Design; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors*; D006801:Humans; D020128:Inhibitory Concentration 50; D017572:Leukotriene A4 / Q000378:metabolism; D008956:Models, Chemical; D011392:Proline / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds / Q000494:pharmacology*; D053778:Thiazolidines / Q000494:pharmacology*
D002264:Carboxylic Acids; D017572:Leukotriene A4; D013438:Sulfhydryl Compounds; D053778:Thiazolidines; D011392:Proline; D004851:Epoxide Hydrolases; C043134:leukotriene A4 hydrolase