Synthesis, further biological evaluation and pharmacodynamics of newly discovered inhibitors of TNF-alpha production.
(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.
Matsui
Toshiaki
T
Fukui Research Institute, Ono Pharmaceutical Co., Ltd., Technoport, Yamagishi, Mikuni, Sakai, Fukui 913-0032, Japan. matsui@ono.co.jp
Kondo
Takashi
T
Nakatani
Shingo
S
Omawari
Nagashige
N
Sakai
Masaru
M
Mori
Hideaki
H
Ogata
Akihito
A
Kato
Junya
J
Ohno
Hiroyuki
H
Obata
Takaaki
T
Nakai
Hisao
H
Toda
Masaaki
M
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
D000605:Amino Alcohols; D009363:Neoplasm Proteins; D047889:Receptors, Tumor Necrosis Factor, Type II; D053319:Tumor Necrosis Factor Decoy Receptors; D014409:Tumor Necrosis Factor-alpha