Discovery and Optimization of Non-bile Acid FXR Agonists as Preclinical Candidates for the Treatment of Nonalcoholic Steatohepatitis

Abstract

Farnesoid X receptor (FXR) plays a key role in bile acid homeostasis, inflammation, fibrosis, and metabolism of lipid and glucose and becomes a promising therapeutic target for nonalcoholic steatohepatitis (NASH) or other FXR-dependent diseases. The phase III trial results of obeticholic acid demonstrate that the FXR agonists emerge as a promising intervention in patients with NASH and fibrosis, but this bile acid-derived FXR agonist brings severe pruritus and an elevated risk of cardiovascular disease for patients. Herein, we reported our efforts in the discovery of a series of non-bile acid FXR agonists, and 36 compounds were designed and synthesized based on the structure-based drug design and structural optimization strategies. Particularly, compound 42 is a highly potent and selective FXR agonist, along with good pharmacokinetic profiles, high liver distribution, and preferable in vivo efficacy, indicating that it is a potential candidate for the treatment of NASH or other FXR-dependent diseases.

Recent Advances in the Medicinal Chemistry of Farnesoid X Receptor

“…Compound 30 has a good PK profile in rats indicating that it could be used as a preclinical candidate in future studies (Table 4). 100 By examination of the liver distribution and plasma concentration of these compounds, 30 was determined to be the best candidate with optimal liver concentrations of 2342.6 ± 392.9 ng/mL and 612.3 ± 313.9 ng/mL at 1 and 4 h after an oral dose of 3 mg/kg in SD rats. In general, 30 displayed the best pharmacokinetic profile in SD rats, with characteristics such as higher drug exposure, slower plasma clearance rate, and good oral bioavailability (Table 4).…”

Redox‐Dependent Effects in the Physiopathological Role of Bile Acids

“…This evidence enhances the interest in developing FXR activators. Interestingly, some non-BA molecules that can activate FXR have been tested in preclinical studies [137][138][139][140].…”

Synthesis of bioactive fluoropyrrolidinesviacopper(i)-catalysed asymmetric 1,3-dipolar cycloaddition of azomethine ylides

“…As mentioned in the beginning, fluorine factors play a crucial role in biological activity, therefore, to confirm the contribution of fluorine atoms in these structures to the antifungal inhibitory reactivity, corresponding chiral pyrrolidinyl derivatives 3f′ , 3k′ , 3q′ , 4b′ and 4k′ without fluorine atoms at the heterocyclic rings were prepared according to Carretero's methods. 55 The antifungal inhibition results of these contrapositive compounds are summarized in Tables 5 and S2,† and the antifungal activities between fluorinated compounds and their contrasts are quite different; as expected, all the contrapositive samples gave poor results in antifungal experiments. 3f′ showed only approximately half of the inhibition rate of 3f against Sclerotinia sclerotiorum , Pestalotiopsis brown-rot fungi, and Rhizoctonia solani (48.38%, 49.34%, 38.44% and 41.62%).…”

“…Owing to their multiple reactivities, readily available gemdifluorostyrenes 35 can participate in various organic transformations to access structurally diversified fluorocompounds. [36][37][38][39][40][41][42][43] Addition or addition-elimination of nucleophiles or free radicals to gem-difluoro-Affinities at 5-HT 1D receptor Analogue I: R 1 = R 2 = H: IC 50 = 0.3; Analogue II: R 1 = H, R 2 = F: IC 50 = 0.9; Analogue III: R 1 = R 2 = F: IC 50 styrenes could lead to difluorocompounds [44][45][46] and monofluoroalkenes [47][48][49][50][51][52][53][54][55] (Scheme 1a and 1b). Taking advantage of gemdifluorostyrenes as reliable trifluoromethyl (CF 3 ) precursors through F + /Faddition, several cascade reactions have been achieved to access trifluoromethyl compounds (Scheme 1c).…”