The Experts below are selected from a list of 267 Experts worldwide ranked by ideXlab platform
Fumihito Muro - One of the best experts on this subject based on the ideXlab platform.
-
A concise synthesis of a very late antigen-4 antagonist trans-4-[1-[[2,5-dichloro-4-(1-methyl-3-indolylcarboxyamide)phenyl]acetyl]-(4S)-methoxy-(2S)-pyrrolidinylmethoxy]Cyclohexanecarboxylic Acid via reductive etherification.
Chemical & pharmaceutical bulletin, 2012Co-Authors: Jun Chiba, Fumihito Muro, Masaki Setoguchi, Nobuo MachinagaAbstract:This contribution describes a concise synthesis to ethyl trans-[(4S)-methoxy-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylate (2b) as a key intermediate of very late antigen-4 (VLA-4) antagonist trans-4-[1-[[2,5-dichloro-4-(1-methyl-3-indolylcarboxyamide)phenyl]acetyl]-(4S)-methoxy-(2S)-pyrrolidinylmethoxy]Cyclohexanecarboxylic Acid (1). The synthesis employs a reductive etherification as a key reaction using (2S,4S)-1-benzyloxycarbonyl-4-methoxypyrrolidine-2-carboxyaldehyde (12) and trans-4-triethylsilyloxycyclohexanecarboxilic Acid ethyl ester (13b). This synthesis provides 2b in 6 steps with 38% overall yield from commercially available starting material.
-
Discovery of trans-4-[1-[[2,5-Dichloro-4-(1-methyl-3-indolylcarboxamido)phenyl]acetyl]-(4S)-methoxy-(2S)-pyrrolidinylmethoxy]Cyclohexanecarboxylic Acid: an orally active, selective very late antigen-4 antagonist.
Journal of medicinal chemistry, 2009Co-Authors: Fumihito Muro, Shin Iimura, Yoshiyuki Yoneda, Jun Chiba, Toshiyuki Watanabe, Masaki Setoguchi, Yuuichi Sugimoto, Yutaka Iigou, Keiko Matsumoto, Atsushi SatohAbstract:We have focused on optimization of the inadequate pharmacokinetic profile of trans-4-substituted Cyclohexanecarboxylic Acid 5, which is commonly observed in many small molecule very late antigen-4 (VLA-4) antagonists. We modified the lipophilic moiety in 5 and found that reducing the polar surface area of this moiety results in improvement of the PK profile. Consequently, our efforts have led to the discovery of trans-4-[1-[[2,5-dichloro-4-(1-methyl-3-indolylcarboxamido)phenyl]acetyl]-(4S)-methoxy-(2S)-pyrrolidinylmethoxy]Cyclohexanecarboxylic Acid (14e) with potent activity (IC50 = 5.4 nM) and significantly improved bioavailability in rats, dogs, and monkeys (100%, 91%, 68%), which demonstrated excellent oral efficacy in murine and guinea pig models of asthma. Based on its overall profile, compound 14e was progressed into clinical trails. In a single ascending-dose phase I clinical study, compound 14e exhibited favorable oral exposure as expected and had no serious adverse events.
-
A novel and potent VLA-4 antagonist based on trans-4-substituted Cyclohexanecarboxylic Acid.
Bioorganic & medicinal chemistry, 2008Co-Authors: Fumihito Muro, Shin Iimura, Yoshiyuki Yoneda, Jun Chiba, Toshiyuki Watanabe, Masaki Setoguchi, Gensuke Takayama, Mika Yokoyama, Tohru Takashi, Atsushi NakayamaAbstract:During the course of our study, it was revealed that the poor pharmacokinetic properties of a series of benzoic Acid derivatives such as 1 should be attributed to the diphenylurea moiety. Thus, we replaced the diphenylurea moiety in 1 with a 2-(2-methylphenylamino)benzoxazole moiety which mimics the diphenylurea structure. However, this modification resulted in a significant decrease ( 3 , IC 50 = 19 nM) in VLA-4 inhibitory activity compared to 1 (IC 50 = 1.6 nM). To address this discrepancy, we worked on optimization of the carboxylic Acid moiety in compound 3 . As a result, our efforts have led to the discovery of trans -4-substituted Cyclohexanecarboxylic Acid derivative 11b (IC 50 = 2.8 nM) as a novel and potent VLA-4 antagonist. In addition, compound 11b exhibited favorable pharmacokinetic properties (CL = 3.3 ml/min/kg, F = 51%) in rats.
Jun Chiba - One of the best experts on this subject based on the ideXlab platform.
-
A concise synthesis of a very late antigen-4 antagonist trans-4-[1-[[2,5-dichloro-4-(1-methyl-3-indolylcarboxyamide)phenyl]acetyl]-(4S)-methoxy-(2S)-pyrrolidinylmethoxy]Cyclohexanecarboxylic Acid via reductive etherification.
Chemical & pharmaceutical bulletin, 2012Co-Authors: Jun Chiba, Fumihito Muro, Masaki Setoguchi, Nobuo MachinagaAbstract:This contribution describes a concise synthesis to ethyl trans-[(4S)-methoxy-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylate (2b) as a key intermediate of very late antigen-4 (VLA-4) antagonist trans-4-[1-[[2,5-dichloro-4-(1-methyl-3-indolylcarboxyamide)phenyl]acetyl]-(4S)-methoxy-(2S)-pyrrolidinylmethoxy]Cyclohexanecarboxylic Acid (1). The synthesis employs a reductive etherification as a key reaction using (2S,4S)-1-benzyloxycarbonyl-4-methoxypyrrolidine-2-carboxyaldehyde (12) and trans-4-triethylsilyloxycyclohexanecarboxilic Acid ethyl ester (13b). This synthesis provides 2b in 6 steps with 38% overall yield from commercially available starting material.
-
A Novel Synthetic Approach to Very Late Antigen-4 Antagonist trans-4-(1- ((2,5-Dichloro-4-(1-methyl-3-indolylcarboxyamide)phenyl)acetyl)-(4S)- methoxy-(2S)-pyrrolidinylmethoxy)Cyclohexanecarboxylic Acid via tert- Butyl trans-((4S)-Methoxy-(2S)-pyrrol
Chemical & pharmaceutical bulletin, 2011Co-Authors: Jun Chiba, Nobuo MachinagaAbstract:This contribution describes a novel synthetic approach to very late antigen-4 (VLA-4) antagonist trans-4-[1-[[2,5-dichloro-4-(1-methyl-3-indolylcarboxyamide)phenyl]acetyl]-(4S)-methoxy-(2S)-pyrrolidinylmethoxy]Cyclohexanecarboxylic Acid (1) via tert-butyl trans-[(4S)-methoxy-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylate (2b) as a key intermediate. The synthesis, which includes n-Bu₄NSO₃H that catalyzed basic etherification of 12 and iodine-mediated cyclization to provide the 2,4-disubstituted pyrrolidine frame of 2b, is designed to utilize trans-4-hydroxyCyclohexanecarboxylic Acid (9) as a commercially available starting material.
-
Discovery of trans-4-[1-[[2,5-Dichloro-4-(1-methyl-3-indolylcarboxamido)phenyl]acetyl]-(4S)-methoxy-(2S)-pyrrolidinylmethoxy]Cyclohexanecarboxylic Acid: an orally active, selective very late antigen-4 antagonist.
Journal of medicinal chemistry, 2009Co-Authors: Fumihito Muro, Shin Iimura, Yoshiyuki Yoneda, Jun Chiba, Toshiyuki Watanabe, Masaki Setoguchi, Yuuichi Sugimoto, Yutaka Iigou, Keiko Matsumoto, Atsushi SatohAbstract:We have focused on optimization of the inadequate pharmacokinetic profile of trans-4-substituted Cyclohexanecarboxylic Acid 5, which is commonly observed in many small molecule very late antigen-4 (VLA-4) antagonists. We modified the lipophilic moiety in 5 and found that reducing the polar surface area of this moiety results in improvement of the PK profile. Consequently, our efforts have led to the discovery of trans-4-[1-[[2,5-dichloro-4-(1-methyl-3-indolylcarboxamido)phenyl]acetyl]-(4S)-methoxy-(2S)-pyrrolidinylmethoxy]Cyclohexanecarboxylic Acid (14e) with potent activity (IC50 = 5.4 nM) and significantly improved bioavailability in rats, dogs, and monkeys (100%, 91%, 68%), which demonstrated excellent oral efficacy in murine and guinea pig models of asthma. Based on its overall profile, compound 14e was progressed into clinical trails. In a single ascending-dose phase I clinical study, compound 14e exhibited favorable oral exposure as expected and had no serious adverse events.
-
A novel and potent VLA-4 antagonist based on trans-4-substituted Cyclohexanecarboxylic Acid.
Bioorganic & medicinal chemistry, 2008Co-Authors: Fumihito Muro, Shin Iimura, Yoshiyuki Yoneda, Jun Chiba, Toshiyuki Watanabe, Masaki Setoguchi, Gensuke Takayama, Mika Yokoyama, Tohru Takashi, Atsushi NakayamaAbstract:During the course of our study, it was revealed that the poor pharmacokinetic properties of a series of benzoic Acid derivatives such as 1 should be attributed to the diphenylurea moiety. Thus, we replaced the diphenylurea moiety in 1 with a 2-(2-methylphenylamino)benzoxazole moiety which mimics the diphenylurea structure. However, this modification resulted in a significant decrease ( 3 , IC 50 = 19 nM) in VLA-4 inhibitory activity compared to 1 (IC 50 = 1.6 nM). To address this discrepancy, we worked on optimization of the carboxylic Acid moiety in compound 3 . As a result, our efforts have led to the discovery of trans -4-substituted Cyclohexanecarboxylic Acid derivative 11b (IC 50 = 2.8 nM) as a novel and potent VLA-4 antagonist. In addition, compound 11b exhibited favorable pharmacokinetic properties (CL = 3.3 ml/min/kg, F = 51%) in rats.
Masaki Setoguchi - One of the best experts on this subject based on the ideXlab platform.
-
A concise synthesis of a very late antigen-4 antagonist trans-4-[1-[[2,5-dichloro-4-(1-methyl-3-indolylcarboxyamide)phenyl]acetyl]-(4S)-methoxy-(2S)-pyrrolidinylmethoxy]Cyclohexanecarboxylic Acid via reductive etherification.
Chemical & pharmaceutical bulletin, 2012Co-Authors: Jun Chiba, Fumihito Muro, Masaki Setoguchi, Nobuo MachinagaAbstract:This contribution describes a concise synthesis to ethyl trans-[(4S)-methoxy-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylate (2b) as a key intermediate of very late antigen-4 (VLA-4) antagonist trans-4-[1-[[2,5-dichloro-4-(1-methyl-3-indolylcarboxyamide)phenyl]acetyl]-(4S)-methoxy-(2S)-pyrrolidinylmethoxy]Cyclohexanecarboxylic Acid (1). The synthesis employs a reductive etherification as a key reaction using (2S,4S)-1-benzyloxycarbonyl-4-methoxypyrrolidine-2-carboxyaldehyde (12) and trans-4-triethylsilyloxycyclohexanecarboxilic Acid ethyl ester (13b). This synthesis provides 2b in 6 steps with 38% overall yield from commercially available starting material.
-
Discovery of trans-4-[1-[[2,5-Dichloro-4-(1-methyl-3-indolylcarboxamido)phenyl]acetyl]-(4S)-methoxy-(2S)-pyrrolidinylmethoxy]Cyclohexanecarboxylic Acid: an orally active, selective very late antigen-4 antagonist.
Journal of medicinal chemistry, 2009Co-Authors: Fumihito Muro, Shin Iimura, Yoshiyuki Yoneda, Jun Chiba, Toshiyuki Watanabe, Masaki Setoguchi, Yuuichi Sugimoto, Yutaka Iigou, Keiko Matsumoto, Atsushi SatohAbstract:We have focused on optimization of the inadequate pharmacokinetic profile of trans-4-substituted Cyclohexanecarboxylic Acid 5, which is commonly observed in many small molecule very late antigen-4 (VLA-4) antagonists. We modified the lipophilic moiety in 5 and found that reducing the polar surface area of this moiety results in improvement of the PK profile. Consequently, our efforts have led to the discovery of trans-4-[1-[[2,5-dichloro-4-(1-methyl-3-indolylcarboxamido)phenyl]acetyl]-(4S)-methoxy-(2S)-pyrrolidinylmethoxy]Cyclohexanecarboxylic Acid (14e) with potent activity (IC50 = 5.4 nM) and significantly improved bioavailability in rats, dogs, and monkeys (100%, 91%, 68%), which demonstrated excellent oral efficacy in murine and guinea pig models of asthma. Based on its overall profile, compound 14e was progressed into clinical trails. In a single ascending-dose phase I clinical study, compound 14e exhibited favorable oral exposure as expected and had no serious adverse events.
-
A novel and potent VLA-4 antagonist based on trans-4-substituted Cyclohexanecarboxylic Acid.
Bioorganic & medicinal chemistry, 2008Co-Authors: Fumihito Muro, Shin Iimura, Yoshiyuki Yoneda, Jun Chiba, Toshiyuki Watanabe, Masaki Setoguchi, Gensuke Takayama, Mika Yokoyama, Tohru Takashi, Atsushi NakayamaAbstract:During the course of our study, it was revealed that the poor pharmacokinetic properties of a series of benzoic Acid derivatives such as 1 should be attributed to the diphenylurea moiety. Thus, we replaced the diphenylurea moiety in 1 with a 2-(2-methylphenylamino)benzoxazole moiety which mimics the diphenylurea structure. However, this modification resulted in a significant decrease ( 3 , IC 50 = 19 nM) in VLA-4 inhibitory activity compared to 1 (IC 50 = 1.6 nM). To address this discrepancy, we worked on optimization of the carboxylic Acid moiety in compound 3 . As a result, our efforts have led to the discovery of trans -4-substituted Cyclohexanecarboxylic Acid derivative 11b (IC 50 = 2.8 nM) as a novel and potent VLA-4 antagonist. In addition, compound 11b exhibited favorable pharmacokinetic properties (CL = 3.3 ml/min/kg, F = 51%) in rats.
Shin Iimura - One of the best experts on this subject based on the ideXlab platform.
-
Discovery of trans-4-[1-[[2,5-Dichloro-4-(1-methyl-3-indolylcarboxamido)phenyl]acetyl]-(4S)-methoxy-(2S)-pyrrolidinylmethoxy]Cyclohexanecarboxylic Acid: an orally active, selective very late antigen-4 antagonist.
Journal of medicinal chemistry, 2009Co-Authors: Fumihito Muro, Shin Iimura, Yoshiyuki Yoneda, Jun Chiba, Toshiyuki Watanabe, Masaki Setoguchi, Yuuichi Sugimoto, Yutaka Iigou, Keiko Matsumoto, Atsushi SatohAbstract:We have focused on optimization of the inadequate pharmacokinetic profile of trans-4-substituted Cyclohexanecarboxylic Acid 5, which is commonly observed in many small molecule very late antigen-4 (VLA-4) antagonists. We modified the lipophilic moiety in 5 and found that reducing the polar surface area of this moiety results in improvement of the PK profile. Consequently, our efforts have led to the discovery of trans-4-[1-[[2,5-dichloro-4-(1-methyl-3-indolylcarboxamido)phenyl]acetyl]-(4S)-methoxy-(2S)-pyrrolidinylmethoxy]Cyclohexanecarboxylic Acid (14e) with potent activity (IC50 = 5.4 nM) and significantly improved bioavailability in rats, dogs, and monkeys (100%, 91%, 68%), which demonstrated excellent oral efficacy in murine and guinea pig models of asthma. Based on its overall profile, compound 14e was progressed into clinical trails. In a single ascending-dose phase I clinical study, compound 14e exhibited favorable oral exposure as expected and had no serious adverse events.
-
A novel and potent VLA-4 antagonist based on trans-4-substituted Cyclohexanecarboxylic Acid.
Bioorganic & medicinal chemistry, 2008Co-Authors: Fumihito Muro, Shin Iimura, Yoshiyuki Yoneda, Jun Chiba, Toshiyuki Watanabe, Masaki Setoguchi, Gensuke Takayama, Mika Yokoyama, Tohru Takashi, Atsushi NakayamaAbstract:During the course of our study, it was revealed that the poor pharmacokinetic properties of a series of benzoic Acid derivatives such as 1 should be attributed to the diphenylurea moiety. Thus, we replaced the diphenylurea moiety in 1 with a 2-(2-methylphenylamino)benzoxazole moiety which mimics the diphenylurea structure. However, this modification resulted in a significant decrease ( 3 , IC 50 = 19 nM) in VLA-4 inhibitory activity compared to 1 (IC 50 = 1.6 nM). To address this discrepancy, we worked on optimization of the carboxylic Acid moiety in compound 3 . As a result, our efforts have led to the discovery of trans -4-substituted Cyclohexanecarboxylic Acid derivative 11b (IC 50 = 2.8 nM) as a novel and potent VLA-4 antagonist. In addition, compound 11b exhibited favorable pharmacokinetic properties (CL = 3.3 ml/min/kg, F = 51%) in rats.
Yoshiyuki Yoneda - One of the best experts on this subject based on the ideXlab platform.
-
Discovery of trans-4-[1-[[2,5-Dichloro-4-(1-methyl-3-indolylcarboxamido)phenyl]acetyl]-(4S)-methoxy-(2S)-pyrrolidinylmethoxy]Cyclohexanecarboxylic Acid: an orally active, selective very late antigen-4 antagonist.
Journal of medicinal chemistry, 2009Co-Authors: Fumihito Muro, Shin Iimura, Yoshiyuki Yoneda, Jun Chiba, Toshiyuki Watanabe, Masaki Setoguchi, Yuuichi Sugimoto, Yutaka Iigou, Keiko Matsumoto, Atsushi SatohAbstract:We have focused on optimization of the inadequate pharmacokinetic profile of trans-4-substituted Cyclohexanecarboxylic Acid 5, which is commonly observed in many small molecule very late antigen-4 (VLA-4) antagonists. We modified the lipophilic moiety in 5 and found that reducing the polar surface area of this moiety results in improvement of the PK profile. Consequently, our efforts have led to the discovery of trans-4-[1-[[2,5-dichloro-4-(1-methyl-3-indolylcarboxamido)phenyl]acetyl]-(4S)-methoxy-(2S)-pyrrolidinylmethoxy]Cyclohexanecarboxylic Acid (14e) with potent activity (IC50 = 5.4 nM) and significantly improved bioavailability in rats, dogs, and monkeys (100%, 91%, 68%), which demonstrated excellent oral efficacy in murine and guinea pig models of asthma. Based on its overall profile, compound 14e was progressed into clinical trails. In a single ascending-dose phase I clinical study, compound 14e exhibited favorable oral exposure as expected and had no serious adverse events.
-
A novel and potent VLA-4 antagonist based on trans-4-substituted Cyclohexanecarboxylic Acid.
Bioorganic & medicinal chemistry, 2008Co-Authors: Fumihito Muro, Shin Iimura, Yoshiyuki Yoneda, Jun Chiba, Toshiyuki Watanabe, Masaki Setoguchi, Gensuke Takayama, Mika Yokoyama, Tohru Takashi, Atsushi NakayamaAbstract:During the course of our study, it was revealed that the poor pharmacokinetic properties of a series of benzoic Acid derivatives such as 1 should be attributed to the diphenylurea moiety. Thus, we replaced the diphenylurea moiety in 1 with a 2-(2-methylphenylamino)benzoxazole moiety which mimics the diphenylurea structure. However, this modification resulted in a significant decrease ( 3 , IC 50 = 19 nM) in VLA-4 inhibitory activity compared to 1 (IC 50 = 1.6 nM). To address this discrepancy, we worked on optimization of the carboxylic Acid moiety in compound 3 . As a result, our efforts have led to the discovery of trans -4-substituted Cyclohexanecarboxylic Acid derivative 11b (IC 50 = 2.8 nM) as a novel and potent VLA-4 antagonist. In addition, compound 11b exhibited favorable pharmacokinetic properties (CL = 3.3 ml/min/kg, F = 51%) in rats.
