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Discovery of Tropifexor (LJN452), a Highly Potent Non-bile Acid FXR Agonist for the Treatment of Cholestatic Liver Diseases and Nonalcoholic Steatohepatitis (NASH).
J Med Chem. 2017 12 28; 60(24):9960-9973.JM

Abstract

The farnesoid X receptor (FXR) is a nuclear receptor that acts as a master regulator of bile acid metabolism and signaling. Activation of FXR inhibits bile acid synthesis and increases bile acid conjugation, transport, and excretion, thereby protecting the liver from the harmful effects of bile accumulation, leading to considerable interest in FXR as a therapeutic target for the treatment of cholestasis and nonalcoholic steatohepatitis. We identified a novel series of highly potent non-bile acid FXR agonists that introduce a bicyclic nortropine-substituted benzothiazole carboxylic acid moiety onto a trisubstituted isoxazole scaffold. Herein, we report the discovery of 1 (tropifexor, LJN452), a novel and highly potent agonist of FXR. Potent in vivo activity was demonstrated in rodent PD models by measuring the induction of FXR target genes in various tissues. Tropifexor has advanced into phase 2 human clinical trials in patients with NASH and PBC.

Authors+Show Affiliations

Genomics Institute of the Novartis Research Foundation , San Diego, California 92121, United States. Novartis Institutes for Biomedical Research , Emeryville, California 94608, United States.Genomics Institute of the Novartis Research Foundation , San Diego, California 92121, United States.Genomics Institute of the Novartis Research Foundation , San Diego, California 92121, United States.Genomics Institute of the Novartis Research Foundation , San Diego, California 92121, United States.Genomics Institute of the Novartis Research Foundation , San Diego, California 92121, United States.Genomics Institute of the Novartis Research Foundation , San Diego, California 92121, United States.Genomics Institute of the Novartis Research Foundation , San Diego, California 92121, United States.Genomics Institute of the Novartis Research Foundation , San Diego, California 92121, United States.Genomics Institute of the Novartis Research Foundation , San Diego, California 92121, United States.Genomics Institute of the Novartis Research Foundation , San Diego, California 92121, United States.Genomics Institute of the Novartis Research Foundation , San Diego, California 92121, United States.Genomics Institute of the Novartis Research Foundation , San Diego, California 92121, United States.Genomics Institute of the Novartis Research Foundation , San Diego, California 92121, United States.Genomics Institute of the Novartis Research Foundation , San Diego, California 92121, United States.Genomics Institute of the Novartis Research Foundation , San Diego, California 92121, United States.Genomics Institute of the Novartis Research Foundation , San Diego, California 92121, United States.Genomics Institute of the Novartis Research Foundation , San Diego, California 92121, United States.Genomics Institute of the Novartis Research Foundation , San Diego, California 92121, United States.Novartis Institutes for Biomedical Research , Emeryville, California 94608, United States.Genomics Institute of the Novartis Research Foundation , San Diego, California 92121, United States.Genomics Institute of the Novartis Research Foundation , San Diego, California 92121, United States.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

29148806

Citation

Tully, David C., et al. "Discovery of Tropifexor (LJN452), a Highly Potent Non-bile Acid FXR Agonist for the Treatment of Cholestatic Liver Diseases and Nonalcoholic Steatohepatitis (NASH)." Journal of Medicinal Chemistry, vol. 60, no. 24, 2017, pp. 9960-9973.
Tully DC, Rucker PV, Chianelli D, et al. Discovery of Tropifexor (LJN452), a Highly Potent Non-bile Acid FXR Agonist for the Treatment of Cholestatic Liver Diseases and Nonalcoholic Steatohepatitis (NASH). J Med Chem. 2017;60(24):9960-9973.
Tully, D. C., Rucker, P. V., Chianelli, D., Williams, J., Vidal, A., Alper, P. B., Mutnick, D., Bursulaya, B., Schmeits, J., Wu, X., Bao, D., Zoll, J., Kim, Y., Groessl, T., McNamara, P., Seidel, H. M., Molteni, V., Liu, B., Phimister, A., ... Laffitte, B. (2017). Discovery of Tropifexor (LJN452), a Highly Potent Non-bile Acid FXR Agonist for the Treatment of Cholestatic Liver Diseases and Nonalcoholic Steatohepatitis (NASH). Journal of Medicinal Chemistry, 60(24), 9960-9973. https://doi.org/10.1021/acs.jmedchem.7b00907
Tully DC, et al. Discovery of Tropifexor (LJN452), a Highly Potent Non-bile Acid FXR Agonist for the Treatment of Cholestatic Liver Diseases and Nonalcoholic Steatohepatitis (NASH). J Med Chem. 2017 12 28;60(24):9960-9973. PubMed PMID: 29148806.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Discovery of Tropifexor (LJN452), a Highly Potent Non-bile Acid FXR Agonist for the Treatment of Cholestatic Liver Diseases and Nonalcoholic Steatohepatitis (NASH). AU - Tully,David C, AU - Rucker,Paul V, AU - Chianelli,Donatella, AU - Williams,Jennifer, AU - Vidal,Agnès, AU - Alper,Phil B, AU - Mutnick,Daniel, AU - Bursulaya,Badry, AU - Schmeits,James, AU - Wu,Xiangdong, AU - Bao,Dingjiu, AU - Zoll,Jocelyn, AU - Kim,Young, AU - Groessl,Todd, AU - McNamara,Peter, AU - Seidel,H Martin, AU - Molteni,Valentina, AU - Liu,Bo, AU - Phimister,Andrew, AU - Joseph,Sean B, AU - Laffitte,Bryan, Y1 - 2017/12/08/ PY - 2017/11/18/pubmed PY - 2019/4/2/medline PY - 2017/11/18/entrez SP - 9960 EP - 9973 JF - Journal of medicinal chemistry JO - J. Med. Chem. VL - 60 IS - 24 N2 - The farnesoid X receptor (FXR) is a nuclear receptor that acts as a master regulator of bile acid metabolism and signaling. Activation of FXR inhibits bile acid synthesis and increases bile acid conjugation, transport, and excretion, thereby protecting the liver from the harmful effects of bile accumulation, leading to considerable interest in FXR as a therapeutic target for the treatment of cholestasis and nonalcoholic steatohepatitis. We identified a novel series of highly potent non-bile acid FXR agonists that introduce a bicyclic nortropine-substituted benzothiazole carboxylic acid moiety onto a trisubstituted isoxazole scaffold. Herein, we report the discovery of 1 (tropifexor, LJN452), a novel and highly potent agonist of FXR. Potent in vivo activity was demonstrated in rodent PD models by measuring the induction of FXR target genes in various tissues. Tropifexor has advanced into phase 2 human clinical trials in patients with NASH and PBC. SN - 1520-4804 UR - https://www.unboundmedicine.com/medline/citation/29148806/Discovery_of_Tropifexor__LJN452__a_Highly_Potent_Non_bile_Acid_FXR_Agonist_for_the_Treatment_of_Cholestatic_Liver_Diseases_and_Nonalcoholic_Steatohepatitis__NASH__ L2 - https://dx.doi.org/10.1021/acs.jmedchem.7b00907 DB - PRIME DP - Unbound Medicine ER -