Syntheses of potential metabolites of a potent kappa-opioid receptor agonist, TRK-820.
Chemical syntheses of three kinds of potential metabolites of TRK-820, a potent kappa-opioid receptor agonist, were described. One of the potential metabolites 2, 17-N-dealkylated TRK-820, was synthesized starting from noroxycodone through 8 steps in 21% total yield. Glucuronidation of intermediate 10 and compound 1, the free base of TRK-820, was carried out stereoselectively to give 3-O-beta-D-glucuronides 15 and 16 in good yields, respectively. Syntheses of potential conjugated metabolites 3 and 4 were accomplished through 10 steps and 2 steps in 11% and 43% total yields, respectively. Among the potential metabolites of TRK-820, compounds 2 and 4 were identified as metabolites in human hepatocytes. The results of pharmacological studies of compounds 2, 3, and 4 are described.
Kawamura
Kuniaki
K
Pharmaceutical Research Laboratories, Toray Industries Inc., 1111 Tebiro, Kamakura, Kanagawa 248-8555, Japan. Kuniaki_Kawamura@nts.toray.co.jp
Horikiri
Hiromasa
H
Hayakawa
Jun
J
Seki
Chie
C
Yoshizawa
Ken-ichi
K
Umeuchi
Hideo
H
Nagase
Hiroshi
H
D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D009019:Morphinans / Q000138:chemical synthesis* / Q000378:metabolism* / Q000494:pharmacology; D017473:Receptors, Opioid, kappa / Q000819:agonists* / Q000502:physiology; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000378:metabolism* / Q000494:pharmacology
D009019:Morphinans; D017473:Receptors, Opioid, kappa; D013141:Spiro Compounds; C111212:TRK 820