Discovery of BMS-986318, a Potent Nonbile Acid FXR Agonist for the Treatment of Nonalcoholic Steatohepatitis

Carpenter, Joseph; Wu, Gang; Wang, Ying; Cook, Emma N.; Wang, Tao; Sitkoff, Doree; Rossi, Karen A.; Mosure, Kathy; Zhuo, Xianlu; Cao, Gary; Ziegler, Milinda; Azzara, Anthony V.; Krupinski, J.; Soars, Matthew G.; Ellsworth, Bruce A.; Wacker, Dean A.

doi:10.1021/acsmedchemlett.1c00198

Cited by 5 publications

(5 citation statements)

References 22 publications

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“…The FXR activation profile of compound 1 was compared with our previously reported FXR agonist BMS-986318 from the isoxazole series (see Figure ). In the hFXR-Gal4 assay, both compounds were potent with some difference in intrinsic activity. Interestingly, the hFXR-Gal4 activity of isoxazole BMS-986318 corelated well with that measured in Huh-7 cells irrespective of the promoter type, viz.…”

Section: Resultsmentioning

confidence: 99%

Discovery of BMS-986339, a Pharmacologically Differentiated Farnesoid X Receptor Agonist for the Treatment of Nonalcoholic Steatohepatitis

et al. 2022

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While several farnesoid X receptor (FXR) agonists under clinical investigation for the treatment of nonalcoholic steatohepatitis (NASH) have shown beneficial effects, adverse effects such as pruritus and elevation of plasma lipids have limited their clinical efficacy and approvability. Herein, we report the discovery and preclinical evaluation of compound 32 (BMS-986339), a nonbile acid FXR agonist with a pharmacologically distinct profile relative to our previously reported agonist BMS-986318. Compound 32 exhibited potent in vitro and in vivo activation of FXR, albeit with a context-dependent profile that resulted in tissue-selective effects in vivo. To our knowledge, this is the first report that demonstrates differential induction of Fgf15 in the liver and ileum by FXR agonists in vivo. Compound 32 demonstrated robust antifibrotic efficacy despite reduced activation of certain genes in the liver, suggesting that the additional pharmacology of BMS-986318 does not further benefit efficacy, possibly presenting an opportunity for reduced adverse effects. Further evaluation in humans is warranted to validate this hypothesis.

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Section: Resultsmentioning

confidence: 99%

Discovery of BMS-986339, a Pharmacologically Differentiated Farnesoid X Receptor Agonist for the Treatment of Nonalcoholic Steatohepatitis

et al. 2022

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“… , Researchers from Glaxo-SmithKline (GSK) reported the first nonbile acid FXR full agonist, GW4064, but its liabilities such as low oral bioavailability, potential toxicity and UV light instability limited its development and restricted it to serve as a tool compound . Subsequently, extensive optimization efforts around GW4064 have resulted in structurally different partial and full FXR agonists (Figure ) ,, with improved overall drug-like properties. Among them, such as Cilofexor (GS-9674), TERN-101, and Tropifexor (LJN452), have progressed into clinical trials and are currently in various stages.…”

Section: Resultsmentioning

confidence: 99%

Discovery of HPG1860, a Structurally Novel Nonbile Acid FXR Agonist Currently in Clinical Development for the Treatment of Nonalcoholic Steatohepatitis

Zhang

et al. 2023

J. Med. Chem.

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The farnesoid X receptor (FXR) is a ligand-activated nuclear receptor. Activation of FXR significantly impacts the expressions of the pivotal genes involved in bile acid metabolism, inflammation, fibrosis, and homeostasis of lipid and glucose, leading to considerable interests in developing FXR agonists for the treatment of nonalcoholic steatohepatitis (NASH) or other FXR-relevant diseases. Herein, we describe the design, optimization, and characterization of a series of N-methylene-piperazinyl derivatives as the nonbile acid FXR agonists. Particularly, compound 23 (HPG1860), a potent full FXR agonist, shows high selectivity, favorable ADME and pharmacokinetics profile, along with favorable in vivo activities demonstrated in both rodent PD model and HFD-CCl4 model and is currently in clinical development in patients with NASH in phase II.

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“…560,561 Other isoxazole FXR agonists such as BMS-986318 (Bristol Myers Squibb) and the more recent BMS-986339 (Bristol Myers Squibb) have been discovered as high potency FXR agonists. 562,563 The last major molecule of the isoxazole family is HPG1860 (Hepagene Therapeutics). 564 Besides that of GW4064 derivative scaffolds, WAY-362450 (Wyeth Pharmaceuticals which was acquired by Pfizer) is a potent full FXR agonist but is horribly insoluble and has been tested only in mice.…”

Section: Druggable Targets Ba Pharmacology Fxr Modulatorsmentioning

confidence: 99%

“…582 BMS-986318 and BMS-986339 have both been found to strongly activate FXR-mediated antifibrotic effects in mice bile duct ligation NASH models. 562,563 LH-10, licraside, and Compound 27 were all found to ameliorate α-napthylisothiocyanate (ANIT) mice model cholestasis. 571,573,574 HPG1860 was found to prevent CCl 4 -induced NASH model inflammation, steatosis, ballooning, and fibrosis similar in effect to OCA.…”

Section: Druggable Targets Ba Pharmacology Fxr Modulatorsmentioning

confidence: 99%

Bile acid metabolism and signaling in health and disease: molecular mechanisms and therapeutic targets

Fleishman,

Kumar

2024

Sig Transduct Target Ther

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Bile acids, once considered mere dietary surfactants, now emerge as critical modulators of macronutrient (lipid, carbohydrate, protein) metabolism and the systemic pro-inflammatory/anti-inflammatory balance. Bile acid metabolism and signaling pathways play a crucial role in protecting against, or if aberrant, inducing cardiometabolic, inflammatory, and neoplastic conditions, strongly influencing health and disease. No curative treatment exists for any bile acid influenced disease, while the most promising and well-developed bile acid therapeutic was recently rejected by the FDA. Here, we provide a bottom-up approach on bile acids, mechanistically explaining their biochemistry, physiology, and pharmacology at canonical and non-canonical receptors. Using this mechanistic model of bile acids, we explain how abnormal bile acid physiology drives disease pathogenesis, emphasizing how ceramide synthesis may serve as a unifying pathogenic feature for cardiometabolic diseases. We provide an in-depth summary on pre-existing bile acid receptor modulators, explain their shortcomings, and propose solutions for how they may be remedied. Lastly, we rationalize novel targets for further translational drug discovery and provide future perspectives. Rather than dismissing bile acid therapeutics due to recent setbacks, we believe that there is immense clinical potential and a high likelihood for the future success of bile acid therapeutics.

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Discovery of BMS-986318, a Potent Nonbile Acid FXR Agonist for the Treatment of Nonalcoholic Steatohepatitis

Cited by 5 publications

References 22 publications

Discovery of BMS-986339, a Pharmacologically Differentiated Farnesoid X Receptor Agonist for the Treatment of Nonalcoholic Steatohepatitis

Discovery of BMS-986339, a Pharmacologically Differentiated Farnesoid X Receptor Agonist for the Treatment of Nonalcoholic Steatohepatitis

Discovery of HPG1860, a Structurally Novel Nonbile Acid FXR Agonist Currently in Clinical Development for the Treatment of Nonalcoholic Steatohepatitis

Bile acid metabolism and signaling in health and disease: molecular mechanisms and therapeutic targets

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