title: Design and synthesis of a metabolically stable and potent antitussive agent, a novel delta opioid receptor antagonist, TRK-851.
abstract: We have previously reported on antitussive effect of (5R,9R,13S,14S)-17-cyclopropylmethyl-6,7-didehydro-4,5-epoxy-5',6'-dihydro-3-methoxy-4'H-pyrrolo[3,2,1-ij]quinolino[2',1':6,7]morphinan-14-ol(1b) methanesulfonate (TRK-850), a selective delta opioid receptor antagonist which markedly reduced the number of coughs in a rat cough model. We designed TRK-850 based on naltrindole (NTI), a typical delta opioid receptor antagonist, to improve its permeability through the blood-brain barrier by introducing hydrophobic moieties to NTI. The ED(50) values of NTI and compound 1b by intraperitoneal injections were 104 microg/kg and 2.07 microg/kg, respectively. This increased antitussive potency probably resulted from the improved brain exposure of compound 1b. However, 1b was extremely unstable toward metabolism by cytochrome P450. In this study, we designed and synthesized compound 1b derivatives to improve the metabolic instability, which resulted in affording highly potent and metabolically stable oral antitussive agent (5R,9R,13S,14S)-17-cyclopropylmethyl-6,7-didehydro-4,5-epoxy-8'-fluoro-5',6'-dihydro-4'H-pyrrolo[3,2,1-ij]quinolino[2',1':6,7]morphinan-3,14-diol (1c) methanesulfonate (TRK-851).
authors.affiliation: Pharmaceutical Research Laboratories, Toray Industries, Inc., 6-10-1 Tebiro, Kamakura, Kanagawa 248-8555, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Sakami
authors.forename: Koji
authors.initials: K
authors.lastname: Kawai
authors.forename: Masayuki
authors.initials: M
authors.lastname: Maeda
authors.forename: Takumi
authors.initials: T
authors.lastname: Aoki
authors.forename: Hideaki
authors.initials: H
authors.lastname: Fujii
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ohno
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Ito
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Saitoh
authors.forename: Kaoru
authors.initials: K
authors.lastname: Nakao
authors.forename: Naoki
authors.initials: N
authors.lastname: Izumimoto
authors.forename: Hirotoshi
authors.initials: H
authors.lastname: Matsuura
authors.forename: Takashi
authors.initials: T
authors.lastname: Endo
authors.forename: Shinya
authors.initials: S
authors.lastname: Ueno
authors.forename: Kazuto
authors.initials: K
authors.lastname: Natsume
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nagase
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000996:Antitussive Agents / Q000008:administration & dosage* / Q000138:chemical synthesis* / Q000737:chemistry; D002211:Capsaicin; D003371:Cough / Q000139:chemically induced / Q000188:drug therapy; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008968:Molecular Conformation; D009271:Naltrexone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D017465:Receptors, Opioid, delta / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C532662:17-cyclopropylmethyl-6,7-didehydro-4,5-epoxy-5',6'-dihydro-3-methoxy-4'H-pyrrolo(3,2,1-ij)quinolino(2',1'-6,7)morphinan-14-ol; C532661:17-cyclopropylmethyl-6,7-didehydro-4,5-epoxy-8'-fluoro-5',6'-dihydro-4'H-pyrrolo(3,2,1-ij)quinolino(2',1'-6,7)morphinan-3,14-diol; D000996:Antitussive Agents; D017465:Receptors, Opioid, delta; D009271:Naltrexone; D002211:Capsaicin