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Title: Discovery of an Oxybenzylglycine Based Peroxisome Proliferator Activated Receptor [alpha] Selective Agonist 2-((3-((2-(4-Chlorophenyl)-5-methyloxazol-4-yl)methoxy)benzyl)(methoxycarbonyl)amino)acetic Acid (BMS-687453)

Abstract

An 1,3-oxybenzylglycine based compound 2 (BMS-687453) was discovered to be a potent and selective peroxisome proliferator activated receptor (PPAR) {alpha} agonist, with an EC{sub 50} of 10 nM for human PPAR{alpha} and 410-fold selectivity vs human PPAR{gamma} in PPAR-GAL4 transactivation assays. Similar potencies and selectivity were also observed in the full length receptor co-transfection assays. Compound 2 has negligible cross-reactivity against a panel of human nuclear hormone receptors including PPAR{delta}. Compound 2 demonstrated an excellent pharmacological and safety profile in preclinical studies and thus was chosen as a development candidate for the treatment of atherosclerosis and dyslipidemia. The X-ray cocrystal structures of the early lead compound 12 and compound 2 in complex with PPAR{alpha} ligand binding domain (LBD) were determined. The role of the crystal structure of compound 12 with PPAR{alpha} in the development of the SAR that ultimately resulted in the discovery of compound 2 is discussed.

Authors:
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  1. BMS
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
USDOE
OSTI Identifier:
1002346
Resource Type:
Journal Article
Journal Name:
J. Med. Chem.
Additional Journal Information:
Journal Volume: 53; Journal Issue: (7) ; 04, 2010; Journal ID: ISSN 0022-2623
Country of Publication:
United States
Language:
ENGLISH
Subject:
36 MATERIALS SCIENCE; ARTERIOSCLEROSIS; CRYSTAL STRUCTURE; HORMONES; LEAD COMPOUNDS; SAFETY

Citation Formats

Li, Jun, Kennedy, Lawrence J, Shi, Yan, Tao, Shiwei, Ye, Xiang-Yang, Chen, Stephanie Y, Wang, Ying, Hernndez, Andrs S, Wang, Wei, Devasthale, Pratik V, Chen, Sean, Lai, Zhi, Zhang, Hao, Wu, Shung, Smirk, Rebecca A, Bolton, Scott A, Ryono, Denis E, Zhang, Huiping, Lim, Ngiap-Kie, Chen, Bang-Chi, Locke, Kenneth T, O’Malley, Kevin M, Zhang, Litao, Srivastava, Rai Ajit, Miao, Bowman, Meyers, Daniel S, Monshizadegan, Hossain, Search, Debra, Grimm, Denise, Zhang, Rongan, Harrity, Thomas, Kunselman, Lori K, Cap, Michael, Kadiyala, Pathanjali, Hosagrahara, Vinayak, Zhang, Lisa, Xu, Carrie, Li, Yi-Xin, Muckelbauer, Jodi K, Chang, Chiehying, An, Yongmi, Krystek, Stanley R, Blanar, Michael A, Zahler, Robert, Mukherjee, Ranjan, Cheng, Peter T.W., and Tino, Joseph A. Discovery of an Oxybenzylglycine Based Peroxisome Proliferator Activated Receptor [alpha] Selective Agonist 2-((3-((2-(4-Chlorophenyl)-5-methyloxazol-4-yl)methoxy)benzyl)(methoxycarbonyl)amino)acetic Acid (BMS-687453). United States: N. p., 2010. Web. doi:10.1021/jm9016812.
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Li, Jun, Kennedy, Lawrence J, Shi, Yan, Tao, Shiwei, Ye, Xiang-Yang, Chen, Stephanie Y, Wang, Ying, Hernndez, Andrs S, Wang, Wei, Devasthale, Pratik V, Chen, Sean, Lai, Zhi, Zhang, Hao, Wu, Shung, Smirk, Rebecca A, Bolton, Scott A, Ryono, Denis E, Zhang, Huiping, Lim, Ngiap-Kie, Chen, Bang-Chi, Locke, Kenneth T, O’Malley, Kevin M, Zhang, Litao, Srivastava, Rai Ajit, Miao, Bowman, Meyers, Daniel S, Monshizadegan, Hossain, Search, Debra, Grimm, Denise, Zhang, Rongan, Harrity, Thomas, Kunselman, Lori K, Cap, Michael, Kadiyala, Pathanjali, Hosagrahara, Vinayak, Zhang, Lisa, Xu, Carrie, Li, Yi-Xin, Muckelbauer, Jodi K, Chang, Chiehying, An, Yongmi, Krystek, Stanley R, Blanar, Michael A, Zahler, Robert, Mukherjee, Ranjan, Cheng, Peter T.W., & Tino, Joseph A. Discovery of an Oxybenzylglycine Based Peroxisome Proliferator Activated Receptor [alpha] Selective Agonist 2-((3-((2-(4-Chlorophenyl)-5-methyloxazol-4-yl)methoxy)benzyl)(methoxycarbonyl)amino)acetic Acid (BMS-687453). United States. https://doi.org/10.1021/jm9016812
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Li, Jun, Kennedy, Lawrence J, Shi, Yan, Tao, Shiwei, Ye, Xiang-Yang, Chen, Stephanie Y, Wang, Ying, Hernndez, Andrs S, Wang, Wei, Devasthale, Pratik V, Chen, Sean, Lai, Zhi, Zhang, Hao, Wu, Shung, Smirk, Rebecca A, Bolton, Scott A, Ryono, Denis E, Zhang, Huiping, Lim, Ngiap-Kie, Chen, Bang-Chi, Locke, Kenneth T, O’Malley, Kevin M, Zhang, Litao, Srivastava, Rai Ajit, Miao, Bowman, Meyers, Daniel S, Monshizadegan, Hossain, Search, Debra, Grimm, Denise, Zhang, Rongan, Harrity, Thomas, Kunselman, Lori K, Cap, Michael, Kadiyala, Pathanjali, Hosagrahara, Vinayak, Zhang, Lisa, Xu, Carrie, Li, Yi-Xin, Muckelbauer, Jodi K, Chang, Chiehying, An, Yongmi, Krystek, Stanley R, Blanar, Michael A, Zahler, Robert, Mukherjee, Ranjan, Cheng, Peter T.W., and Tino, Joseph A. 2010. "Discovery of an Oxybenzylglycine Based Peroxisome Proliferator Activated Receptor [alpha] Selective Agonist 2-((3-((2-(4-Chlorophenyl)-5-methyloxazol-4-yl)methoxy)benzyl)(methoxycarbonyl)amino)acetic Acid (BMS-687453)". United States. https://doi.org/10.1021/jm9016812.
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@article{osti_1002346,
title = {Discovery of an Oxybenzylglycine Based Peroxisome Proliferator Activated Receptor [alpha] Selective Agonist 2-((3-((2-(4-Chlorophenyl)-5-methyloxazol-4-yl)methoxy)benzyl)(methoxycarbonyl)amino)acetic Acid (BMS-687453)},
author = {Li, Jun and Kennedy, Lawrence J and Shi, Yan and Tao, Shiwei and Ye, Xiang-Yang and Chen, Stephanie Y and Wang, Ying and Hernndez, Andrs S and Wang, Wei and Devasthale, Pratik V and Chen, Sean and Lai, Zhi and Zhang, Hao and Wu, Shung and Smirk, Rebecca A and Bolton, Scott A and Ryono, Denis E and Zhang, Huiping and Lim, Ngiap-Kie and Chen, Bang-Chi and Locke, Kenneth T and O’Malley, Kevin M and Zhang, Litao and Srivastava, Rai Ajit and Miao, Bowman and Meyers, Daniel S and Monshizadegan, Hossain and Search, Debra and Grimm, Denise and Zhang, Rongan and Harrity, Thomas and Kunselman, Lori K and Cap, Michael and Kadiyala, Pathanjali and Hosagrahara, Vinayak and Zhang, Lisa and Xu, Carrie and Li, Yi-Xin and Muckelbauer, Jodi K and Chang, Chiehying and An, Yongmi and Krystek, Stanley R and Blanar, Michael A and Zahler, Robert and Mukherjee, Ranjan and Cheng, Peter T.W. and Tino, Joseph A},
abstractNote = {An 1,3-oxybenzylglycine based compound 2 (BMS-687453) was discovered to be a potent and selective peroxisome proliferator activated receptor (PPAR) {alpha} agonist, with an EC{sub 50} of 10 nM for human PPAR{alpha} and 410-fold selectivity vs human PPAR{gamma} in PPAR-GAL4 transactivation assays. Similar potencies and selectivity were also observed in the full length receptor co-transfection assays. Compound 2 has negligible cross-reactivity against a panel of human nuclear hormone receptors including PPAR{delta}. Compound 2 demonstrated an excellent pharmacological and safety profile in preclinical studies and thus was chosen as a development candidate for the treatment of atherosclerosis and dyslipidemia. The X-ray cocrystal structures of the early lead compound 12 and compound 2 in complex with PPAR{alpha} ligand binding domain (LBD) were determined. The role of the crystal structure of compound 12 with PPAR{alpha} in the development of the SAR that ultimately resulted in the discovery of compound 2 is discussed.},
doi = {10.1021/jm9016812},
url = {https://www.osti.gov/biblio/1002346}, journal = {J. Med. Chem.},
issn = {0022-2623},
number = (7) ; 04, 2010,
volume = 53,
place = {United States},
year = {Mon Apr 12 00:00:00 EDT 2010},
month = {Mon Apr 12 00:00:00 EDT 2010}
}
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Journal Article:
https://doi.org/10.1021/jm9016812
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