Journal of Medicinal Chemistry, volume 58, issue 24, pages 9768-9772
Discovery of 6-(4-{[5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl]methoxy}piperidin-1-yl)-1-methyl-1H-indole-3-carboxylic Acid: A Novel FXR Agonist for the Treatment of Dyslipidemia
Michaël Genin
,
Ana B Bueno
,
Javier Agejas Francisco
,
Peter R Manninen
,
Wayne P. Bocchinfuso
,
Chahrzad Montrose-Rafizadeh
,
Ellen A Cannady
,
Timothy M. Jones
,
John R Stille
1
,
Eyas Raddad
1
,
Charles Reidy
,
Amy Cox
,
M.Dodson Michael
,
Laura F. Michael
1
Chorus, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, United States
|
Publication type: Journal Article
Publication date: 2015-12-02
Journal:
Journal of Medicinal Chemistry
Quartile SCImago
Q1
Quartile WOS
Q1
Impact factor: 7.3
ISSN: 00222623, 15204804
Drug Discovery
Molecular Medicine
Abstract
The farnesoid X receptor (FXR) is a member of the "metabolic" subfamily of nuclear receptors. Several FXR agonists have been reported in the literature to have profound effects on plasma lipids in animal models. To discover novel and effective therapies for dyslipidemia and atherosclerosis, we have developed a series of potent FXR agonists that robustly lower plasma LDL and vLDL in LDLr-/- mice. To this end the novel piperidinylisoxazole system LY2562175 was discovered. This molecule is a potent and selective FXR agonist in vitro and has robust lipid modulating properties, lowering LDL and triglycerides while raising HDL in preclinical species. The preclinical ADME properties of LY2562175 were consistent with enabling once daily dosing in humans, and it was ultimately advanced to the clinic for evaluation in humans. The synthesis and biological profile of this molecule is discussed.
Top-30
Citations by journals
|
1
2
3
4
5
6
7
|
|
|
Journal of Medicinal Chemistry
7 publications, 14.58%
|
|
|
Bioorganic and Medicinal Chemistry
4 publications, 8.33%
|
|
|
Bioorganic and Medicinal Chemistry Letters
4 publications, 8.33%
|
|
|
Molecules
3 publications, 6.25%
|
|
|
Frontiers in Pharmacology
3 publications, 6.25%
|
|
|
European Journal of Medicinal Chemistry
3 publications, 6.25%
|
|
|
Handbook of Experimental Pharmacology
1 publication, 2.08%
|
|
|
Experimental and Molecular Medicine
1 publication, 2.08%
|
|
|
Metabolites
1 publication, 2.08%
|
|
|
Scientific Reports
1 publication, 2.08%
|
|
|
Acta Pharmacologica Sinica
1 publication, 2.08%
|
|
|
Nature Communications
1 publication, 2.08%
|
|
|
Medicinal Chemistry Research
1 publication, 2.08%
|
|
|
Biomedicine and Pharmacotherapy
1 publication, 2.08%
|
|
|
Molecular and Cellular Endocrinology
1 publication, 2.08%
|
|
|
Journal of Lipid Research
1 publication, 2.08%
|
|
|
Tetrahedron
1 publication, 2.08%
|
|
|
Tetrahedron Asymmetry
1 publication, 2.08%
|
|
|
Computational and Structural Biotechnology Journal
1 publication, 2.08%
|
|
|
Chinese Journal of Chemistry
1 publication, 2.08%
|
|
|
Clinical Pharmacology in Drug Development
1 publication, 2.08%
|
|
|
Organic Process Research and Development
1 publication, 2.08%
|
|
|
RSC Chemical Biology
1 publication, 2.08%
|
|
|
ChemMedChem
1 publication, 2.08%
|
|
|
Journal of Hepatology
1 publication, 2.08%
|
|
|
Journal of Flow Chemistry
1 publication, 2.08%
|
|
|
Expert Opinion on Therapeutic Patents
1 publication, 2.08%
|
|
|
Signal Transduction and Targeted Therapy
1 publication, 2.08%
|
|
|
1
2
3
4
5
6
7
|
Citations by publishers
|
2
4
6
8
10
12
14
16
18
|
|
|
Elsevier
17 publications, 35.42%
|
|
|
American Chemical Society (ACS)
8 publications, 16.67%
|
|
|
Springer Nature
7 publications, 14.58%
|
|
|
Multidisciplinary Digital Publishing Institute (MDPI)
4 publications, 8.33%
|
|
|
Wiley
4 publications, 8.33%
|
|
|
Frontiers Media S.A.
3 publications, 6.25%
|
|
|
American Society for Biochemistry and Molecular Biology
1 publication, 2.08%
|
|
|
Royal Society of Chemistry (RSC)
1 publication, 2.08%
|
|
|
Akademiai Kiado
1 publication, 2.08%
|
|
|
Taylor & Francis
1 publication, 2.08%
|
|
|
2
4
6
8
10
12
14
16
18
|
- We do not take into account publications without a DOI.
- Statistics recalculated only for publications connected to researchers, organizations and labs registered on the platform.
- Statistics recalculated weekly.
{"yearsCitations":{"type":"bar","data":{"show":true,"labels":[2017,2018,2019,2020,2021,2022,2023,2024],"ids":[0,0,0,0,0,0,0,0],"codes":[0,0,0,0,0,0,0,0],"imageUrls":["","","","","","","",""],"datasets":[{"label":"Citations number","data":[6,4,3,9,10,7,6,3],"backgroundColor":["#3B82F6","#3B82F6","#3B82F6","#3B82F6","#3B82F6","#3B82F6","#3B82F6","#3B82F6"],"percentage":["12.5","8.33","6.25","18.75","20.83","14.58","12.5","6.25"],"barThickness":null}]},"options":{"indexAxis":"x","maintainAspectRatio":true,"scales":{"y":{"ticks":{"precision":0,"autoSkip":false,"font":{"family":"Montserrat"},"color":"#000000"},"stacked":false},"x":{"ticks":{"stepSize":1,"precision":0,"font":{"family":"Montserrat"},"color":"#000000"},"stacked":false}},"plugins":{"legend":{"position":"top","labels":{"font":{"family":"Montserrat"},"color":"#000000"}},"title":{"display":true,"text":"Citations per year","font":{"size":24,"family":"Montserrat","weight":600},"color":"#000000"}}}},"journals":{"type":"bar","data":{"show":true,"labels":["Journal of Medicinal Chemistry","Bioorganic and Medicinal Chemistry","Bioorganic and Medicinal Chemistry Letters","Molecules","Frontiers in Pharmacology","European Journal of Medicinal Chemistry","Handbook of Experimental Pharmacology","Experimental and Molecular Medicine","Metabolites","Scientific Reports","Acta Pharmacologica Sinica","Nature Communications","Medicinal Chemistry Research","Biomedicine and Pharmacotherapy","Molecular and Cellular Endocrinology","Journal of Lipid Research","Tetrahedron","Tetrahedron Asymmetry","Computational and Structural Biotechnology Journal","Chinese Journal of Chemistry","Clinical Pharmacology in Drug Development","Organic Process Research and Development","RSC Chemical Biology","ChemMedChem","Journal of Hepatology","Journal of Flow Chemistry","Expert Opinion on Therapeutic Patents","Signal Transduction and Targeted Therapy"],"ids":[3673,1162,8828,1770,9788,8171,4844,23547,17024,13767,13018,3231,6106,23951,3552,8542,3439,23178,4268,7222,10634,11058,27133,1430,1532,5228,6211,10186],"codes":[0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0],"imageUrls":["\/storage\/images\/resized\/iLiQsFqFaSEx6chlGQ5fbAwF6VYU3WWa08hkss0g_medium.webp","\/storage\/images\/resized\/GDnYOu1UpMMfMMRV6Aqle4H0YLLsraeD9IP9qScG_medium.webp","\/storage\/images\/resized\/GDnYOu1UpMMfMMRV6Aqle4H0YLLsraeD9IP9qScG_medium.webp","\/storage\/images\/resized\/MjH1ITP7lMYGxeqUZfkt2BnVLgjkk413jwBV97XX_medium.webp","\/storage\/images\/resized\/4QWA67eqfcfyOiA8Wk7YnqroHFqQbTsmDJUYTCTg_medium.webp","\/storage\/images\/resized\/GDnYOu1UpMMfMMRV6Aqle4H0YLLsraeD9IP9qScG_medium.webp","\/storage\/images\/resized\/voXLqlsvTwv5p3iMQ8Dhs95nqB4AXOG7Taj7G4ra_medium.webp","\/storage\/images\/resized\/voXLqlsvTwv5p3iMQ8Dhs95nqB4AXOG7Taj7G4ra_medium.webp","\/storage\/images\/resized\/MjH1ITP7lMYGxeqUZfkt2BnVLgjkk413jwBV97XX_medium.webp","\/storage\/images\/resized\/voXLqlsvTwv5p3iMQ8Dhs95nqB4AXOG7Taj7G4ra_medium.webp","\/storage\/images\/resized\/voXLqlsvTwv5p3iMQ8Dhs95nqB4AXOG7Taj7G4ra_medium.webp","\/storage\/images\/resized\/voXLqlsvTwv5p3iMQ8Dhs95nqB4AXOG7Taj7G4ra_medium.webp","\/storage\/images\/resized\/voXLqlsvTwv5p3iMQ8Dhs95nqB4AXOG7Taj7G4ra_medium.webp","\/storage\/images\/resized\/GDnYOu1UpMMfMMRV6Aqle4H0YLLsraeD9IP9qScG_medium.webp","\/storage\/images\/resized\/GDnYOu1UpMMfMMRV6Aqle4H0YLLsraeD9IP9qScG_medium.webp","\/storage\/images\/resized\/OuA6WPZekwEiUM99mP2pSqj4yHPxHezM6xgLhAjO_medium.webp","\/storage\/images\/resized\/GDnYOu1UpMMfMMRV6Aqle4H0YLLsraeD9IP9qScG_medium.webp","\/storage\/images\/resized\/GDnYOu1UpMMfMMRV6Aqle4H0YLLsraeD9IP9qScG_medium.webp","\/storage\/images\/resized\/GDnYOu1UpMMfMMRV6Aqle4H0YLLsraeD9IP9qScG_medium.webp","\/storage\/images\/resized\/bRyGpdm98BkAUYiK1YFNpl5Z7hPu6Gd87gbIeuG3_medium.webp","\/storage\/images\/resized\/bRyGpdm98BkAUYiK1YFNpl5Z7hPu6Gd87gbIeuG3_medium.webp","\/storage\/images\/resized\/iLiQsFqFaSEx6chlGQ5fbAwF6VYU3WWa08hkss0g_medium.webp","\/storage\/images\/resized\/leiAYcRDGTSl5B1eCnwpSGqmDEUEfDPPoYisFGhT_medium.webp","\/storage\/images\/resized\/bRyGpdm98BkAUYiK1YFNpl5Z7hPu6Gd87gbIeuG3_medium.webp","\/storage\/images\/resized\/GDnYOu1UpMMfMMRV6Aqle4H0YLLsraeD9IP9qScG_medium.webp","\/storage\/images\/resized\/lZ7ODGrM6PfzyKRLOh0nsqTcgHBMMYr9TkD5skBH_medium.webp","\/storage\/images\/resized\/5YZtvLvkPZuc2JHOaZsjCvGSHFCuC3drUwN3YAc5_medium.webp","\/storage\/images\/resized\/voXLqlsvTwv5p3iMQ8Dhs95nqB4AXOG7Taj7G4ra_medium.webp"],"datasets":[{"label":"","data":[7,4,4,3,3,3,1,1,1,1,1,1,1,1,1,1,1,1,1,1,1,1,1,1,1,1,1,1],"backgroundColor":["#3B82F6","#3B82F6","#3B82F6","#3B82F6","#3B82F6","#3B82F6","#3B82F6","#3B82F6","#3B82F6","#3B82F6","#3B82F6","#3B82F6","#3B82F6","#3B82F6","#3B82F6","#3B82F6","#3B82F6","#3B82F6","#3B82F6","#3B82F6","#3B82F6","#3B82F6","#3B82F6","#3B82F6","#3B82F6","#3B82F6","#3B82F6","#3B82F6"],"percentage":[14.58,8.33,8.33,6.25,6.25,6.25,2.08,2.08,2.08,2.08,2.08,2.08,2.08,2.08,2.08,2.08,2.08,2.08,2.08,2.08,2.08,2.08,2.08,2.08,2.08,2.08,2.08,2.08],"barThickness":13}]},"options":{"indexAxis":"y","maintainAspectRatio":false,"scales":{"y":{"ticks":{"precision":0,"autoSkip":false,"font":{"family":"Montserrat"},"color":"#000000"},"stacked":false},"x":{"ticks":{"stepSize":null,"precision":0,"font":{"family":"Montserrat"},"color":"#000000"},"stacked":false}},"plugins":{"legend":{"position":"top","labels":{"font":{"family":"Montserrat"},"color":"#000000"}},"title":{"display":true,"text":"Journals","font":{"size":24,"family":"Montserrat","weight":600},"color":"#000000"}}}},"publishers":{"type":"bar","data":{"show":true,"labels":["Elsevier","American Chemical Society (ACS)","Springer Nature","Multidisciplinary Digital Publishing Institute (MDPI)","Wiley","Frontiers Media S.A.","American Society for Biochemistry and Molecular Biology","Royal Society of Chemistry (RSC)","Akademiai Kiado","Taylor & Francis"],"ids":[17,40,8,202,11,208,2090,123,7012,18],"codes":[0,0,0,0,0,0,0,0,0,0],"imageUrls":["\/storage\/images\/resized\/GDnYOu1UpMMfMMRV6Aqle4H0YLLsraeD9IP9qScG_medium.webp","\/storage\/images\/resized\/iLiQsFqFaSEx6chlGQ5fbAwF6VYU3WWa08hkss0g_medium.webp","\/storage\/images\/resized\/voXLqlsvTwv5p3iMQ8Dhs95nqB4AXOG7Taj7G4ra_medium.webp","\/storage\/images\/resized\/MjH1ITP7lMYGxeqUZfkt2BnVLgjkk413jwBV97XX_medium.webp","\/storage\/images\/resized\/bRyGpdm98BkAUYiK1YFNpl5Z7hPu6Gd87gbIeuG3_medium.webp","\/storage\/images\/resized\/4QWA67eqfcfyOiA8Wk7YnqroHFqQbTsmDJUYTCTg_medium.webp","\/storage\/images\/resized\/OuA6WPZekwEiUM99mP2pSqj4yHPxHezM6xgLhAjO_medium.webp","\/storage\/images\/resized\/leiAYcRDGTSl5B1eCnwpSGqmDEUEfDPPoYisFGhT_medium.webp","\/storage\/images\/resized\/lZ7ODGrM6PfzyKRLOh0nsqTcgHBMMYr9TkD5skBH_medium.webp","\/storage\/images\/resized\/5YZtvLvkPZuc2JHOaZsjCvGSHFCuC3drUwN3YAc5_medium.webp"],"datasets":[{"label":"","data":[17,8,7,4,4,3,1,1,1,1],"backgroundColor":["#3B82F6","#3B82F6","#3B82F6","#3B82F6","#3B82F6","#3B82F6","#3B82F6","#3B82F6","#3B82F6","#3B82F6"],"percentage":[35.42,16.67,14.58,8.33,8.33,6.25,2.08,2.08,2.08,2.08],"barThickness":13}]},"options":{"indexAxis":"y","maintainAspectRatio":false,"scales":{"y":{"ticks":{"precision":0,"autoSkip":false,"font":{"family":"Montserrat"},"color":"#000000"},"stacked":false},"x":{"ticks":{"stepSize":null,"precision":0,"font":{"family":"Montserrat"},"color":"#000000"},"stacked":false}},"plugins":{"legend":{"position":"top","labels":{"font":{"family":"Montserrat"},"color":"#000000"}},"title":{"display":true,"text":"Publishers","font":{"size":24,"family":"Montserrat","weight":600},"color":"#000000"}}}}}
Are you a researcher?
Create a profile to get free access to personal recommendations for colleagues and new articles.
Metrics
Cite this
GOST |
RIS |
BibTex |
MLA
Cite this
GOST
Copy
Genin M. et al. Discovery of 6-(4-{[5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl]methoxy}piperidin-1-yl)-1-methyl-1H-indole-3-carboxylic Acid: A Novel FXR Agonist for the Treatment of Dyslipidemia // Journal of Medicinal Chemistry. 2015. Vol. 58. No. 24. pp. 9768-9772.
GOST all authors (up to 50)
Copy
Genin M., Bueno A. B., Agejas Francisco J., Manninen P. R., Bocchinfuso W. P., Montrose-Rafizadeh C., Cannady E. A., Jones T. M., Stille J. R., Raddad E., Reidy C., Cox A., Michael M., Michael L. F. Discovery of 6-(4-{[5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl]methoxy}piperidin-1-yl)-1-methyl-1H-indole-3-carboxylic Acid: A Novel FXR Agonist for the Treatment of Dyslipidemia // Journal of Medicinal Chemistry. 2015. Vol. 58. No. 24. pp. 9768-9772.
Cite this
RIS
Copy
TY - JOUR
DO - 10.1021/acs.jmedchem.5b01161
UR - https://doi.org/10.1021/acs.jmedchem.5b01161
TI - Discovery of 6-(4-{[5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl]methoxy}piperidin-1-yl)-1-methyl-1H-indole-3-carboxylic Acid: A Novel FXR Agonist for the Treatment of Dyslipidemia
T2 - Journal of Medicinal Chemistry
AU - Agejas Francisco, Javier
AU - Manninen, Peter R
AU - Bocchinfuso, Wayne P.
AU - Montrose-Rafizadeh, Chahrzad
AU - Cannady, Ellen A
AU - Jones, Timothy M.
AU - Raddad, Eyas
AU - Reidy, Charles
AU - Cox, Amy
AU - Genin, Michaël
AU - Bueno, Ana B
AU - Stille, John R
AU - Michael, M.Dodson
AU - Michael, Laura F.
PY - 2015
DA - 2015/12/02
PB - American Chemical Society (ACS)
SP - 9768-9772
IS - 24
VL - 58
SN - 0022-2623
SN - 1520-4804
ER -
Cite this
BibTex
Copy
@article{2015_Genin,
author = {Javier Agejas Francisco and Peter R Manninen and Wayne P. Bocchinfuso and Chahrzad Montrose-Rafizadeh and Ellen A Cannady and Timothy M. Jones and Eyas Raddad and Charles Reidy and Amy Cox and Michaël Genin and Ana B Bueno and John R Stille and M.Dodson Michael and Laura F. Michael},
title = {Discovery of 6-(4-{[5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl]methoxy}piperidin-1-yl)-1-methyl-1H-indole-3-carboxylic Acid: A Novel FXR Agonist for the Treatment of Dyslipidemia},
journal = {Journal of Medicinal Chemistry},
year = {2015},
volume = {58},
publisher = {American Chemical Society (ACS)},
month = {dec},
url = {https://doi.org/10.1021/acs.jmedchem.5b01161},
number = {24},
pages = {9768--9772},
doi = {10.1021/acs.jmedchem.5b01161}
}
Cite this
MLA
Copy
Genin, Michaël, et al. “Discovery of 6-(4-{[5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl]methoxy}piperidin-1-yl)-1-methyl-1H-indole-3-carboxylic Acid: A Novel FXR Agonist for the Treatment of Dyslipidemia.” Journal of Medicinal Chemistry, vol. 58, no. 24, Dec. 2015, pp. 9768-9772. https://doi.org/10.1021/acs.jmedchem.5b01161.