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Takashi Sugane - One of the best experts on this subject based on the ideXlab platform.
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atropisomeric 4 phenyl 4h 1 2 4 triazoles as selective Glycine Transporter 1 inhibitors
Journal of Medicinal Chemistry, 2013Co-Authors: Takashi Sugane, Takahiko Tobe, Wataru Hamaguchi, Itsuro Shimada, Kyoichi Maeno, Junji Miyata, Takeshi Suzuki, Tetsuya Kimizuka, Shuichi Sakamoto, Shinichi TsukamotoAbstract:We report on the optimization of 4H-1,2,4-triazole derivatives to increase their activity and selectivity as Glycine Transporter 1 (GlyT1) inhibitors. Structure–activity relationship exploration resulted in the identification of a 3-[3-ethyl-5-(6-phenylpyridin-3-yl)-4H-1,2,4-triazol-4-yl]-2-methylbenzonitrile (14u) compound with markedly higher selectivity for GlyT1. Physiochemical studies revealed that 14u exists as a stable pair of atropisomers under physiological conditions. We successfully separated the atropisomers to obtain active enantiomer (R)-14u, which displayed favorable pharmacokinetic properties, as well as positive results in the mice Y-maze test.
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synthesis and biological evaluation of 4h 1 2 4 triazol 4 yl isoquinoline derivatives as selective Glycine Transporter 1 inhibitors
Bioorganic & Medicinal Chemistry, 2012Co-Authors: Takashi Sugane, Takahiko Tobe, Wataru Hamaguchi, Itsuro Shimada, Kyoichi Maeno, Junji Miyata, Takeshi Suzuki, Tetsuya Kimizuka, Takuma Morita, Shuichi SakamotoAbstract:Abstract To identify novel Glycine Transporter 1(GlyT1) inhibitors with greater selectivity relative to GlyT2 and improved aqueous solubility, we synthesized a series of 4H-1,2,4-triazole derivatives with heteroaromatic rings at the 4-position and investigated their structure–activity relationships. Replacement of the 2-fluorophenyl group of lead compound 5 with various aromatic groups led to the identification of 5-(3-biphenyl-4-yl-5-ethyl-4H-1,2,4-triazol-4-yl)isoquinoline (15) with 38-fold selectivity between GlyT1 and GlyT2. 15 also showed improved aqueous solubility and in vivo efficacy on (+)-HA966-induced hyperlocomotion in mice over the lead compound.
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synthesis and biological evaluation of 3 biphenyl 4 yl 4 phenyl 4h 1 2 4 triazoles as novel Glycine Transporter 1 inhibitors
Journal of Medicinal Chemistry, 2011Co-Authors: Takashi Sugane, Takahiko Tobe, Wataru Hamaguchi, Itsuro Shimada, Kyoichi Maeno, Junji Miyata, Takeshi Suzuki, Tetsuya Kimizuka, Atsuyuki Kohara, Takuma MoritaAbstract:We describe the preparation and evaluation of a novel series of Glycine Transporter 1 (GlyT1) inhibitors derived from a high-throughput screening hit. The SAR studies resulted in the discovery of 3-biphenyl-4-yl-4-(2-fluorophenyl)-5-isopropyl-4H-1,2,4-triazole (6p). A pharmacokinetic study was also conducted and revealed that 6p had excellent oral bioavailability and ameliorated learning impairment in passive avoidance tasks in mice.
Tetsuya Kimizuka - One of the best experts on this subject based on the ideXlab platform.
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atropisomeric 4 phenyl 4h 1 2 4 triazoles as selective Glycine Transporter 1 inhibitors
Journal of Medicinal Chemistry, 2013Co-Authors: Takashi Sugane, Takahiko Tobe, Wataru Hamaguchi, Itsuro Shimada, Kyoichi Maeno, Junji Miyata, Takeshi Suzuki, Tetsuya Kimizuka, Shuichi Sakamoto, Shinichi TsukamotoAbstract:We report on the optimization of 4H-1,2,4-triazole derivatives to increase their activity and selectivity as Glycine Transporter 1 (GlyT1) inhibitors. Structure–activity relationship exploration resulted in the identification of a 3-[3-ethyl-5-(6-phenylpyridin-3-yl)-4H-1,2,4-triazol-4-yl]-2-methylbenzonitrile (14u) compound with markedly higher selectivity for GlyT1. Physiochemical studies revealed that 14u exists as a stable pair of atropisomers under physiological conditions. We successfully separated the atropisomers to obtain active enantiomer (R)-14u, which displayed favorable pharmacokinetic properties, as well as positive results in the mice Y-maze test.
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synthesis and biological evaluation of 4h 1 2 4 triazol 4 yl isoquinoline derivatives as selective Glycine Transporter 1 inhibitors
Bioorganic & Medicinal Chemistry, 2012Co-Authors: Takashi Sugane, Takahiko Tobe, Wataru Hamaguchi, Itsuro Shimada, Kyoichi Maeno, Junji Miyata, Takeshi Suzuki, Tetsuya Kimizuka, Takuma Morita, Shuichi SakamotoAbstract:Abstract To identify novel Glycine Transporter 1(GlyT1) inhibitors with greater selectivity relative to GlyT2 and improved aqueous solubility, we synthesized a series of 4H-1,2,4-triazole derivatives with heteroaromatic rings at the 4-position and investigated their structure–activity relationships. Replacement of the 2-fluorophenyl group of lead compound 5 with various aromatic groups led to the identification of 5-(3-biphenyl-4-yl-5-ethyl-4H-1,2,4-triazol-4-yl)isoquinoline (15) with 38-fold selectivity between GlyT1 and GlyT2. 15 also showed improved aqueous solubility and in vivo efficacy on (+)-HA966-induced hyperlocomotion in mice over the lead compound.
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synthesis and biological evaluation of 3 biphenyl 4 yl 4 phenyl 4h 1 2 4 triazoles as novel Glycine Transporter 1 inhibitors
Journal of Medicinal Chemistry, 2011Co-Authors: Takashi Sugane, Takahiko Tobe, Wataru Hamaguchi, Itsuro Shimada, Kyoichi Maeno, Junji Miyata, Takeshi Suzuki, Tetsuya Kimizuka, Atsuyuki Kohara, Takuma MoritaAbstract:We describe the preparation and evaluation of a novel series of Glycine Transporter 1 (GlyT1) inhibitors derived from a high-throughput screening hit. The SAR studies resulted in the discovery of 3-biphenyl-4-yl-4-(2-fluorophenyl)-5-isopropyl-4H-1,2,4-triazole (6p). A pharmacokinetic study was also conducted and revealed that 6p had excellent oral bioavailability and ameliorated learning impairment in passive avoidance tasks in mice.
Takeshi Suzuki - One of the best experts on this subject based on the ideXlab platform.
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atropisomeric 4 phenyl 4h 1 2 4 triazoles as selective Glycine Transporter 1 inhibitors
Journal of Medicinal Chemistry, 2013Co-Authors: Takashi Sugane, Takahiko Tobe, Wataru Hamaguchi, Itsuro Shimada, Kyoichi Maeno, Junji Miyata, Takeshi Suzuki, Tetsuya Kimizuka, Shuichi Sakamoto, Shinichi TsukamotoAbstract:We report on the optimization of 4H-1,2,4-triazole derivatives to increase their activity and selectivity as Glycine Transporter 1 (GlyT1) inhibitors. Structure–activity relationship exploration resulted in the identification of a 3-[3-ethyl-5-(6-phenylpyridin-3-yl)-4H-1,2,4-triazol-4-yl]-2-methylbenzonitrile (14u) compound with markedly higher selectivity for GlyT1. Physiochemical studies revealed that 14u exists as a stable pair of atropisomers under physiological conditions. We successfully separated the atropisomers to obtain active enantiomer (R)-14u, which displayed favorable pharmacokinetic properties, as well as positive results in the mice Y-maze test.
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synthesis and biological evaluation of 4h 1 2 4 triazol 4 yl isoquinoline derivatives as selective Glycine Transporter 1 inhibitors
Bioorganic & Medicinal Chemistry, 2012Co-Authors: Takashi Sugane, Takahiko Tobe, Wataru Hamaguchi, Itsuro Shimada, Kyoichi Maeno, Junji Miyata, Takeshi Suzuki, Tetsuya Kimizuka, Takuma Morita, Shuichi SakamotoAbstract:Abstract To identify novel Glycine Transporter 1(GlyT1) inhibitors with greater selectivity relative to GlyT2 and improved aqueous solubility, we synthesized a series of 4H-1,2,4-triazole derivatives with heteroaromatic rings at the 4-position and investigated their structure–activity relationships. Replacement of the 2-fluorophenyl group of lead compound 5 with various aromatic groups led to the identification of 5-(3-biphenyl-4-yl-5-ethyl-4H-1,2,4-triazol-4-yl)isoquinoline (15) with 38-fold selectivity between GlyT1 and GlyT2. 15 also showed improved aqueous solubility and in vivo efficacy on (+)-HA966-induced hyperlocomotion in mice over the lead compound.
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synthesis and biological evaluation of 3 biphenyl 4 yl 4 phenyl 4h 1 2 4 triazoles as novel Glycine Transporter 1 inhibitors
Journal of Medicinal Chemistry, 2011Co-Authors: Takashi Sugane, Takahiko Tobe, Wataru Hamaguchi, Itsuro Shimada, Kyoichi Maeno, Junji Miyata, Takeshi Suzuki, Tetsuya Kimizuka, Atsuyuki Kohara, Takuma MoritaAbstract:We describe the preparation and evaluation of a novel series of Glycine Transporter 1 (GlyT1) inhibitors derived from a high-throughput screening hit. The SAR studies resulted in the discovery of 3-biphenyl-4-yl-4-(2-fluorophenyl)-5-isopropyl-4H-1,2,4-triazole (6p). A pharmacokinetic study was also conducted and revealed that 6p had excellent oral bioavailability and ameliorated learning impairment in passive avoidance tasks in mice.
Junji Miyata - One of the best experts on this subject based on the ideXlab platform.
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atropisomeric 4 phenyl 4h 1 2 4 triazoles as selective Glycine Transporter 1 inhibitors
Journal of Medicinal Chemistry, 2013Co-Authors: Takashi Sugane, Takahiko Tobe, Wataru Hamaguchi, Itsuro Shimada, Kyoichi Maeno, Junji Miyata, Takeshi Suzuki, Tetsuya Kimizuka, Shuichi Sakamoto, Shinichi TsukamotoAbstract:We report on the optimization of 4H-1,2,4-triazole derivatives to increase their activity and selectivity as Glycine Transporter 1 (GlyT1) inhibitors. Structure–activity relationship exploration resulted in the identification of a 3-[3-ethyl-5-(6-phenylpyridin-3-yl)-4H-1,2,4-triazol-4-yl]-2-methylbenzonitrile (14u) compound with markedly higher selectivity for GlyT1. Physiochemical studies revealed that 14u exists as a stable pair of atropisomers under physiological conditions. We successfully separated the atropisomers to obtain active enantiomer (R)-14u, which displayed favorable pharmacokinetic properties, as well as positive results in the mice Y-maze test.
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synthesis and biological evaluation of 4h 1 2 4 triazol 4 yl isoquinoline derivatives as selective Glycine Transporter 1 inhibitors
Bioorganic & Medicinal Chemistry, 2012Co-Authors: Takashi Sugane, Takahiko Tobe, Wataru Hamaguchi, Itsuro Shimada, Kyoichi Maeno, Junji Miyata, Takeshi Suzuki, Tetsuya Kimizuka, Takuma Morita, Shuichi SakamotoAbstract:Abstract To identify novel Glycine Transporter 1(GlyT1) inhibitors with greater selectivity relative to GlyT2 and improved aqueous solubility, we synthesized a series of 4H-1,2,4-triazole derivatives with heteroaromatic rings at the 4-position and investigated their structure–activity relationships. Replacement of the 2-fluorophenyl group of lead compound 5 with various aromatic groups led to the identification of 5-(3-biphenyl-4-yl-5-ethyl-4H-1,2,4-triazol-4-yl)isoquinoline (15) with 38-fold selectivity between GlyT1 and GlyT2. 15 also showed improved aqueous solubility and in vivo efficacy on (+)-HA966-induced hyperlocomotion in mice over the lead compound.
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synthesis and biological evaluation of 3 biphenyl 4 yl 4 phenyl 4h 1 2 4 triazoles as novel Glycine Transporter 1 inhibitors
Journal of Medicinal Chemistry, 2011Co-Authors: Takashi Sugane, Takahiko Tobe, Wataru Hamaguchi, Itsuro Shimada, Kyoichi Maeno, Junji Miyata, Takeshi Suzuki, Tetsuya Kimizuka, Atsuyuki Kohara, Takuma MoritaAbstract:We describe the preparation and evaluation of a novel series of Glycine Transporter 1 (GlyT1) inhibitors derived from a high-throughput screening hit. The SAR studies resulted in the discovery of 3-biphenyl-4-yl-4-(2-fluorophenyl)-5-isopropyl-4H-1,2,4-triazole (6p). A pharmacokinetic study was also conducted and revealed that 6p had excellent oral bioavailability and ameliorated learning impairment in passive avoidance tasks in mice.
Kyoichi Maeno - One of the best experts on this subject based on the ideXlab platform.
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atropisomeric 4 phenyl 4h 1 2 4 triazoles as selective Glycine Transporter 1 inhibitors
Journal of Medicinal Chemistry, 2013Co-Authors: Takashi Sugane, Takahiko Tobe, Wataru Hamaguchi, Itsuro Shimada, Kyoichi Maeno, Junji Miyata, Takeshi Suzuki, Tetsuya Kimizuka, Shuichi Sakamoto, Shinichi TsukamotoAbstract:We report on the optimization of 4H-1,2,4-triazole derivatives to increase their activity and selectivity as Glycine Transporter 1 (GlyT1) inhibitors. Structure–activity relationship exploration resulted in the identification of a 3-[3-ethyl-5-(6-phenylpyridin-3-yl)-4H-1,2,4-triazol-4-yl]-2-methylbenzonitrile (14u) compound with markedly higher selectivity for GlyT1. Physiochemical studies revealed that 14u exists as a stable pair of atropisomers under physiological conditions. We successfully separated the atropisomers to obtain active enantiomer (R)-14u, which displayed favorable pharmacokinetic properties, as well as positive results in the mice Y-maze test.
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synthesis and biological evaluation of 4h 1 2 4 triazol 4 yl isoquinoline derivatives as selective Glycine Transporter 1 inhibitors
Bioorganic & Medicinal Chemistry, 2012Co-Authors: Takashi Sugane, Takahiko Tobe, Wataru Hamaguchi, Itsuro Shimada, Kyoichi Maeno, Junji Miyata, Takeshi Suzuki, Tetsuya Kimizuka, Takuma Morita, Shuichi SakamotoAbstract:Abstract To identify novel Glycine Transporter 1(GlyT1) inhibitors with greater selectivity relative to GlyT2 and improved aqueous solubility, we synthesized a series of 4H-1,2,4-triazole derivatives with heteroaromatic rings at the 4-position and investigated their structure–activity relationships. Replacement of the 2-fluorophenyl group of lead compound 5 with various aromatic groups led to the identification of 5-(3-biphenyl-4-yl-5-ethyl-4H-1,2,4-triazol-4-yl)isoquinoline (15) with 38-fold selectivity between GlyT1 and GlyT2. 15 also showed improved aqueous solubility and in vivo efficacy on (+)-HA966-induced hyperlocomotion in mice over the lead compound.
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synthesis and biological evaluation of 3 biphenyl 4 yl 4 phenyl 4h 1 2 4 triazoles as novel Glycine Transporter 1 inhibitors
Journal of Medicinal Chemistry, 2011Co-Authors: Takashi Sugane, Takahiko Tobe, Wataru Hamaguchi, Itsuro Shimada, Kyoichi Maeno, Junji Miyata, Takeshi Suzuki, Tetsuya Kimizuka, Atsuyuki Kohara, Takuma MoritaAbstract:We describe the preparation and evaluation of a novel series of Glycine Transporter 1 (GlyT1) inhibitors derived from a high-throughput screening hit. The SAR studies resulted in the discovery of 3-biphenyl-4-yl-4-(2-fluorophenyl)-5-isopropyl-4H-1,2,4-triazole (6p). A pharmacokinetic study was also conducted and revealed that 6p had excellent oral bioavailability and ameliorated learning impairment in passive avoidance tasks in mice.