title: Synthesis, further biological evaluation and pharmacodynamics of newly discovered inhibitors of TNF-alpha production.
abstract: (1S,2R)-2-Acylamino-1-methyl-2-phenylethyl phosphate derivatives 2a, 2b, 3a, and 5a, which are conformationally restricted and metabolically stable analogues of (2R)-2-acylamino-2-phenylethyl phosphate derivatives 1a and 1b, are a new class of inhibitors of TNF-alpha production. More efficient alternative synthesis of a key intermediate, (1R,2S)-1-amino-1-(3-methoxyphenyl)propan-2-ol hydrochloride (9), was achieved using one-step, three-component coupling of 3-methoxyphenyl boronic acid (13), (5S)-2,2,5-trimethyl-1,3-dioxolan-4-ol (14), and amino diphenyl methane (15), [as reported in J. Am. Chem. Soc. 1998, 120, 11798]. Evaluation of the hypotensive activity of these compounds was done to assess one of their side effects. Among the compounds tested, the above-mentioned four compounds (2a, 2b, 3a, and 5a) were identified as inhibitors with both sufficient potency and an acceptable safety margin regarding their hypotensive activity. The pharmacodynamics of these compounds were also investigated. Single-dose pharmacokinetic data for compounds 2a, 2b, 3a, and 5a are displayed. These compounds were estimated to be mainly metabolized by the liver in the species tested based on their in vitro stability in tissue homogenates and plasma. A representative compound, 2a, showed good linearity of its plasma concentration after intravenous injection.
authors.affiliation: Fukui Research Institute, Ono Pharmaceutical Co., Ltd., Technoport, Yamagishi, Mikuni, Sakai, Fukui 913-0032, Japan. matsui@ono.co.jp
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Matsui
authors.forename: Takashi
authors.initials: T
authors.lastname: Kondo
authors.forename: Shingo
authors.initials: S
authors.lastname: Nakatani
authors.forename: Nagashige
authors.initials: N
authors.lastname: Omawari
authors.forename: Masaru
authors.initials: M
authors.lastname: Sakai
authors.forename: Hideaki
authors.initials: H
authors.lastname: Mori
authors.forename: Akihito
authors.initials: A
authors.lastname: Ogata
authors.forename: Junya
authors.initials: J
authors.lastname: Kato
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Ohno
authors.forename: Takaaki
authors.initials: T
authors.lastname: Obata
authors.forename: Hisao
authors.initials: H
authors.lastname: Nakai
authors.forename: Masaaki
authors.initials: M
authors.lastname: Toda
mesh_terms: D000605:Amino Alcohols / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D019540:Area Under Curve; D001794:Blood Pressure / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004355:Drug Stability; D006207:Half-Life; D006801:Humans; D007022:Hypotension / Q000139:chemically induced; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D009363:Neoplasm Proteins / Q000097:blood / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D047889:Receptors, Tumor Necrosis Factor, Type II; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D053319:Tumor Necrosis Factor Decoy Receptors; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000037:antagonists & inhibitors
chemical_list: D000605:Amino Alcohols; D009363:Neoplasm Proteins; D047889:Receptors, Tumor Necrosis Factor, Type II; D053319:Tumor Necrosis Factor Decoy Receptors; D014409:Tumor Necrosis Factor-alpha