Prodrugs of 3-(3,4-dichlorobenzyloxy)-2-amino-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (MGS0039): a potent and orally active group II mGluR antagonist with antidepressant-like potential.
3-(3,4-Dichlorobenzyloxy)-2-amino-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid 5 (MGS0039) is a highly selective and potent group II metabotropic glutamate receptor (mGluR) antagonist (antagonist activities for mGluR2; IC50=20.0 nM, mGluR3; IC50=24.0 nM) and is detected in both plasma (492 ng/mL) and brain (13.2 ng/g) at oral administration of 10 ng/mL [J. Med. Chem.2004, 47, 4750], but the oral bioavailability of 5 was 10.9%. In order to improve the oral bioavailability of 5, prodrugs of 5 were discovered by esterification of carboxyl group on C6-position of bicyclo[3.1.0]hexane ring. Among these compounds, 6-alkyl esters exhibited approximately 10-fold higher concentrations of 5 in the plasma and brain of rats after oral administration (e.g., ethyl ester of 5; plasma, Cmax=20.7+/-1.3 microM) compared to oral administration of 5 (plasma, Cmax=2.46+/-0.62 microM). 3-(3,4-Dichlorobenzyloxy)-2-amino-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid 6-heptyl ester (7ao), a prodrug of MGS0039, showed antidepressant-like effects in rat forced swimming test and mouse tail suspension test following oral administration. Moreover, following oral administration of 7ao in mice, high concentrations of MGS0039 were detected in both the brain and plasma, while 7ao was barely detected. In this paper, we report the synthesis, in vitro metabolic stabilities, and pharmacokinetic profiles of the prodrugs of 5, and the antidepressant-like effects of 7ao.
Yasuhara
Akito
A
Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd, 1-403 Saitama-shi, Saitama 331-9530, Japan. a.yasuhara@po.rd.taisho.co.jp
Nakamura
Masato
M
Sakagami
Kazunari
K
Shimazaki
Toshiharu
T
Yoshikawa
Ryoko
R
Chaki
Shigeyuki
S
Ohta
Hiroshi
H
Nakazato
Atsuro
A
D000284:Administration, Oral; D000818:Animals; D000928:Antidepressive Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D001682:Biological Availability; D001643:Bridged Bicyclo Compounds / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D003998:Dicarboxylic Acids / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008968:Molecular Conformation; D011355:Prodrugs / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013550:Swimming / Q000502:physiology
C483757:2-amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo(3.1.0)hexane-2,6-dicarboxylic acid; D000928:Antidepressive Agents; D001643:Bridged Bicyclo Compounds; D003998:Dicarboxylic Acids; D011355:Prodrugs; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2; C102718:metabotropic glutamate receptor 3