Design and synthesis of a metabolically stable and potent antitussive agent, a novel delta opioid receptor antagonist, TRK-851.
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).
Sakami
Satoshi
S
Pharmaceutical Research Laboratories, Toray Industries, Inc., 6-10-1 Tebiro, Kamakura, Kanagawa 248-8555, Japan.
Kawai
Koji
K
Maeda
Masayuki
M
Aoki
Takumi
T
Fujii
Hideaki
H
Ohno
Hiroshi
H
Ito
Tsuyoshi
T
Saitoh
Akiyoshi
A
Nakao
Kaoru
K
Izumimoto
Naoki
N
Matsuura
Hirotoshi
H
Endo
Takashi
T
Ueno
Shinya
S
Natsume
Kazuto
K
Nagase
Hiroshi
H
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
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