Synthesis, in vitro pharmacology, structure-activity relationships, and pharmacokinetics of 3-alkoxy-2-amino-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivatives as potent and selective group II metabotropic glutamate receptor antagonists.
Novel group II metabotropic glutamate receptor (mGluR) antagonists, 3-alkoxy-2-amino-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivatives 11 and 12, were discovered by the incorporation of a hydroxy or alkoxyl group onto the C-3 portion of selective and potent group II mGluR agonist 5, (1R,2S,5R,6R)-2-amino-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid. Among these compounds, (1R,2R,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (-)-11be (MGS0039) was a highly selective and potent group II mGluR antagonist with the best pharmacokinetic profile. Compound (-)-11be exhibited high affinities for mGlu 2 (Ki = 2.38 +/- 0.40 nM) and mGlu 3 (4.46 +/- 0.31 nM) but low affinity for mGluR 7 (Ki = 664 +/- 106 nM), and potent antagonist activities for mGlu 2 (IC50 = 20.0 +/- 3.67 nM) and mGluR 3 (IC50 = 24.0 +/- 3.54 nM) but much less potent antagonist activities for mGlu 4 (IC50 = 1740 +/- 1080 nM), mGlu 6 (IC50 = 2060 +/- 1270 nM), mGlu 1 (IC50 = 93300 +/- 14600 nM), and mGluR 5 (IC(50) = 117000 +/- 38600 nM). No significant agonist activities of (-)-11be were found for mGluRs 2, 3, 4, 6, 1, and 5 (EC50 > 100,000 nM). Furthermore, (-)-11be exhibited dose-dependent oral absorption (plasma C(max): 214 +/- 56.7, 932 +/- 235, and 2960 +/- 1150 ng/mL for 3 mg/kg, 10 mg/kg, and 30 mg/kg, po, respectively) and acceptable blood-brain barrier penetration (brain C(max): 13.2 ng/mL for 10 mg/kg, p.o. 6 h). In this paper, we report the synthesis, in vitro pharmacological profile, and structure-activity relationships (SARs) of 3-alkoxy-2-amino-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivatives 11 and 12, and pharmacokinetic profiles of several typical compounds.
Medicinal Chemistry Laboratory, Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd., 1-403 Yoshino-cho, Kita-ku, Saitama-shi, Saitama 331-9530, Japan. atsu.nakazato@po.rd.taisho.co.jp
Atsuro
A
Nakazato
Kazunari
K
Sakagami
Akito
A
Yasuhara
Hiroshi
H
Ohta
Ryoko
R
Yoshikawa
Manabu
M
Itoh
Masato
M
Nakamura
Shigeyuki
S
Chaki
D000284:Administration, Oral; D000600:Amino Acids, Dicarboxylic / Q000138:chemical synthesis* / Q000493:pharmacokinetics* / Q000494:pharmacology; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D010599:Pharmacokinetics; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D000600:Amino Acids, Dicarboxylic; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2