title: Synthesis and biological evaluation of N-mercaptoacylcysteine derivatives as leukotriene A4 hydrolase inhibitors.
abstract: We studied synthetic modifications of N-mercaptoacylamino acid derivatives to develop a new class of leukotriene A(4) (LTA(4)) hydrolase inhibitors. S-(4-Dimethylamino)benzyl-l-cysteine derivative 2a (SA6541) showed inhibitory activity against LTA(4) hydrolase (IC(50), 270nM) and selectivity over other metallopeptidases except angiotensin-converting enzyme (ACE, IC(50), 520nM). Modification at the para-substituent of the phenyl ring of compound 2a improved LTA(4) hydrolase inhibitory activity as well as selectivity over ACE. Finally, we obtained S-(4-cyclohexyl)benzy-l-cysteine derivatives 11l and 16i as potent and selective LTA(4) hydrolase inhibitors.
authors.affiliation: Nara Research & Development Center, Santen Pharmaceutical Co., Ltd, 8916-16 Takayama-cho, Ikoma-shi, Nara 630-0101, Japan. hiroshi.enomoto@santen.co.jp
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Enomoto
authors.forename: Yuko
authors.initials: Y
authors.lastname: Morikawa
authors.forename: Yurika
authors.initials: Y
authors.lastname: Miyake
authors.forename: Fumio
authors.initials: F
authors.lastname: Tsuji
authors.forename: Maki
authors.initials: M
authors.lastname: Mizuchi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Suhara
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Fujimura
authors.forename: Masato
authors.initials: M
authors.lastname: Horiuchi
authors.forename: Masakazu
authors.initials: M
authors.lastname: Ban
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D003545:Cysteine / Q000737:chemistry*; D004353:Drug Evaluation, Preclinical; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D021281:Quantitative Structure-Activity Relationship; D013438:Sulfhydryl Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D013438:Sulfhydryl Compounds; D004851:Epoxide Hydrolases; D003545:Cysteine; C043134:leukotriene A4 hydrolase