In vivo pharmacokinetic study and oral glucose tolerance test of sulfoxide analogs of GPR40 agonist TAK‐875
TAK‐875 (compound 1) was the only GPR40 agonist with promising oral glucose‐lowering effect, which entered phase III clinical trials. In previous studies, we successfully synthesized the TAK‐875 sulfoxide analog 2, which was further separated to optically pure compounds 3 (S, S, 100.0% de) and 4 (R,...
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Published in | Drug development research Vol. 81; no. 6; pp. 708 - 715 |
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01.09.2020
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Abstract | TAK‐875 (compound 1) was the only GPR40 agonist with promising oral glucose‐lowering effect, which entered phase III clinical trials. In previous studies, we successfully synthesized the TAK‐875 sulfoxide analog 2, which was further separated to optically pure compounds 3 (S, S, 100.0% de) and 4 (R, S, 100.0% de). In vitro biological evaluation revealed that the sulfoxide analogs 3 and 4 possessed comparable GPR40 agonist activity to TAK‐875. Herein, in order to further evaluate the druglikeness of TAK‐875 sulfoxide analogs, the pharmacokinetic properties of compounds 2, 3, and 4 in rats were investigated and compared with that of TAK‐875. The results showed that sulfoxide (2, 3, and 4) and sulfone (TAK‐875) could be converted into each other in different degrees in vivo. Interestingly, compound 3 showed higher drug exposure calculated by the AUC sum of sulfoxide and sulfone in plasma than TAK‐875, 2 and 4. In order to further investigate the in vivo glucose‐lowering potency of sulfoxide analogs, asymmetric synthesis was carried out and led to two sulfoxides with moderate de values, 5 (S, S, 66.4% de) and 6 (R, S, 71.0% de). The following oral glucose tolerance test (OGTT) in rats showed that 5 (S, S, 66.4% de) had stronger glucose‐lowering effect in vivo than 6 (R, S, 71.0% de) and TAK‐875, which could be partly rationalized by the superior pharmacokinetic property of sulfoxide 3 (the main component of 5) relative to sulfoxide 4 (the main component of 6) and TAK‐875. |
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AbstractList | TAK‐875 (compound 1) was the only GPR40 agonist with promising oral glucose‐lowering effect, which entered phase III clinical trials. In previous studies, we successfully synthesized the TAK‐875 sulfoxide analog 2, which was further separated to optically pure compounds 3 (S, S, 100.0% de) and 4 (R, S, 100.0% de). In vitro biological evaluation revealed that the sulfoxide analogs 3 and 4 possessed comparable GPR40 agonist activity to TAK‐875. Herein, in order to further evaluate the druglikeness of TAK‐875 sulfoxide analogs, the pharmacokinetic properties of compounds 2, 3, and 4 in rats were investigated and compared with that of TAK‐875. The results showed that sulfoxide (2, 3, and 4) and sulfone (TAK‐875) could be converted into each other in different degrees in vivo. Interestingly, compound 3 showed higher drug exposure calculated by the AUC sum of sulfoxide and sulfone in plasma than TAK‐875, 2 and 4. In order to further investigate the in vivo glucose‐lowering potency of sulfoxide analogs, asymmetric synthesis was carried out and led to two sulfoxides with moderate de values, 5 (S, S, 66.4% de) and 6 (R, S, 71.0% de). The following oral glucose tolerance test (OGTT) in rats showed that 5 (S, S, 66.4% de) had stronger glucose‐lowering effect in vivo than 6 (R, S, 71.0% de) and TAK‐875, which could be partly rationalized by the superior pharmacokinetic property of sulfoxide 3 (the main component of 5) relative to sulfoxide 4 (the main component of 6) and TAK‐875. Abstract TAK‐875 (compound 1 ) was the only GPR40 agonist with promising oral glucose‐lowering effect, which entered phase III clinical trials. In previous studies, we successfully synthesized the TAK‐875 sulfoxide analog 2 , which was further separated to optically pure compounds 3 (S, S, 100.0% de) and 4 (R, S, 100.0% de). In vitro biological evaluation revealed that the sulfoxide analogs 3 and 4 possessed comparable GPR40 agonist activity to TAK‐875. Herein, in order to further evaluate the druglikeness of TAK‐875 sulfoxide analogs, the pharmacokinetic properties of compounds 2 , 3 , and 4 in rats were investigated and compared with that of TAK‐875. The results showed that sulfoxide ( 2 , 3 , and 4 ) and sulfone (TAK‐875) could be converted into each other in different degrees in vivo. Interestingly, compound 3 showed higher drug exposure calculated by the AUC sum of sulfoxide and sulfone in plasma than TAK‐875, 2 and 4 . In order to further investigate the in vivo glucose‐lowering potency of sulfoxide analogs, asymmetric synthesis was carried out and led to two sulfoxides with moderate de values, 5 (S, S, 66.4% de) and 6 (R, S, 71.0% de). The following oral glucose tolerance test (OGTT) in rats showed that 5 (S, S, 66.4% de) had stronger glucose‐lowering effect in vivo than 6 (R, S, 71.0% de) and TAK‐875, which could be partly rationalized by the superior pharmacokinetic property of sulfoxide 3 (the main component of 5 ) relative to sulfoxide 4 (the main component of 6 ) and TAK‐875. |
Author | Yan, Yugang Dong, Hang Zhao, Chunlong Zhang, Yingjie Xu, Qifu Xu, Wenfang |
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Cites_doi | 10.1021/jm3002026 10.1074/jbc.M806987200 10.1007/s12272-013-0283-3 10.1038/s41467-017-01240-w 10.1021/ml500391n 10.1152/ajpendo.00035.2005 10.1517/17460441003605098 10.1038/nature01478 10.6023/cjoc201612041 10.1124/mol.112.079640 10.1016/j.phrs.2020.104679 10.1517/13543770802665717 10.2337/db08-0130 10.1016/j.bmcl.2014.05.019 10.1074/jbc.M211495200 10.1073/pnas.1811066116 10.1016/j.bioorg.2019.103209 10.1021/jm300170m 10.1021/ml1000855 10.1038/nsmb.3417 10.1371/journal.pone.0076280 10.1038/nature13494 10.1016/j.bbrc.2005.07.042 10.1016/j.bmcl.2013.03.060 10.2337/db06-1532 10.1021/jm0614782 |
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Notes | Funding information Yugang Yan and Qifu Xu contributed equally to this work. Key Research and Development Program of Shandong Province, Grant/Award Number: 2017CXGC1401; Natural Science Foundation of Shandong Province, Grant/Award Number: ZR2018QH007; Young Scholars Program of Shandong University, Grant/Award Numbers: YSPSDU, 2016WLJH33 |
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Snippet | TAK‐875 (compound 1) was the only GPR40 agonist with promising oral glucose‐lowering effect, which entered phase III clinical trials. In previous studies, we... TAK-875 (compound 1) was the only GPR40 agonist with promising oral glucose-lowering effect, which entered phase III clinical trials. In previous studies, we... Abstract TAK‐875 (compound 1 ) was the only GPR40 agonist with promising oral glucose‐lowering effect, which entered phase III clinical trials. In previous... |
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SubjectTerms | Agonists Analogs Asymmetric synthesis Clinical trials G protein coupled receptor 40 agonist Glucose Glucose tolerance In vivo methods and tests Pharmacokinetics Pharmacology sulfone sulfoxide Sulfoxides |
Title | In vivo pharmacokinetic study and oral glucose tolerance test of sulfoxide analogs of GPR40 agonist TAK‐875 |
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