367488-49-1Relevant academic research and scientific papers
Synthesis, in vitro pharmacology, and structure-activity relationships of 2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivatives as mGluR2 antagonists
Yasuhara, Akito,Sakagami, Kazunari,Yoshikawa, Ryoko,Chaki, Shigeyuki,Nakamura, Masato,Nakazato, Atsuro
, p. 3405 - 3420 (2007/10/03)
Chemical modification of the bicyclo[3.1.0]hexane ring C-3 position led to the discovery of 3-alkoxy-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid, 3-benzylthio-, and 3-benzylamino-2-amino-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivatives, metabotropic glutamate receptor 2 (mGluR2) antagonists. In particular, 3-(3,4-dichlorobenzyloxy)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (15ae), (1R,2S,5R,6R)-2-amino-3-(3,4-dichlorobenzylthio)-6-fluorobicyclo[3.1.0]h exane-2,6-carboxylic acid (15at), and (1R,2S,5R,6R)-2-amino-3-(N-(3,4-dichlorobenzylamino))-6-fluorobicyclo[3. 1.0]hexane-2,6-carboxylic (15ba) showed high affinity for the mGluR2 receptor (15ae: Ki = 2.51 nM, 15at: Ki = 1.96 nM, and 15ba: Ki = 3.29 nM) and potent antagonist activity for mGluR2 (15ae; IC50 = 34.21 nM, 15at; IC50 = 13.34 nM, and 15ba; IC50 = 35.96 nM). No significant agonist activity for mGluR2 was observed with 15ae, 15at, or 15ba. This paper reports on the synthesis, in vitro pharmacological profile, and structure-activity relationships (SARs) of 3-substituted-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid.
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
Nakazato, Atsuro,Sakagami, Kazunari,Yasuhara, Akito,Ohta, Hiroshi,Yoshikawa, Ryoko,Itoh, Manabu,Nakamura, Masato,Chaki, Shigeyuki
, p. 4570 - 4587 (2007/10/03)
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 ± 3.67nM) 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 (IC50 = 117000 ± 38600 nM). No significant agonist activities of (-)-11be were found for mGluRs 2, 3, 4, 6, 1, and 5 (EC50 > 100000 nM). Furthermore, (-)-11be exhibited dose-dependent oral absorption (plasma Cmax: 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, po 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.
Design and synthesis of potent C2-symmetric diol-based HIV-1 protease inhibitors: Effects of fluoro substitution
Pyring,Lindberg,Rosenquist,Zuccarello,Kvarnstr?m,Zhang,Vrang,Unge,Classon,Hallberg,Samuelsson
, p. 3083 - 3091 (2007/10/03)
Implementation of derivatized carbohydrates as C2-symmetric HIV-1 protease inhibitors has previously been reported. With the objective of improving the anti-HIV activity of such compounds, we synthesized a series of fluoro substituted P1/P1′ an
