Nonacidic Chemotype Possessing N-Acylated Piperidine Moiety as Potent Farnesoid X Receptor (FXR) Antagonists

Abstract

Farnesoid X receptor (FXR) plays a major role in the control of cholesterol metabolism. Antagonizing transcriptional activity of FXR is an effective means to treat the relevant metabolic syndrome. Some of antagonists so far have the charged functions; however, they may negatively affect the pharmacokinetics. We describe herein a structure-activity relationship (SAR) exploration of nonacidic FXR antagonist focusing on two regions in the structure and biological evaluation of nonacidic with the characteristic -acylated piperidine group obtained from SAR studies. As the robust affinity to FXR is feasible with our nonacidic analogue, is among the most promising candidates for testing.

Synthesis of Novel Farnesoid X Receptor Agonists and Validation of Their Efficacy in Activating Differentiation of Mouse Bone Marrow-Derived Mesenchymal Stem Cells into Osteoblasts

“…FXR agonists previously reported by Akwabi-Ameyaw et al have the fused aromatic rings (e.g., benzothiophene or N -nonsubstituted benzimidazole) as the alternative to the stilbene of GW4064 and their compounds reveal the agonistic activity against FXR at nanomolar levels [39]. Encouraged by the observation obtained from the previous report [39], and considering the stability of the derivatives such as benzothiophene (e.g., labile for oxidation) [62] and a wide diversity of the building blocks containing N -substituted benzimidazole moiety [52,53,54], exploring a new series of FXR agonists was initiated. We synthesized four compounds ( 1 – 4 ) to verify the usefulness of the moiety as FXR agonists and determined their potential effects in osteoblast differentiation of ST-2 MSCs.…”

“…The synthetic schemes for novel FXR agonists 1 – 4 were depicted in Supplementry Scheme S1 ( 1 , 2 ) and Scheme 1 ( 3 , 4 ). The isoxazole moiety of GW4064 [34] and N -substituted benzimidazole part [53,54] were prepared according to the previous reports. The isoxazole derivative was coupled with 4-hydroxybenzoate derivatives in DMF containing K 2 CO 3 to yield 3 – 1 and 4 – 1 .…”

“…The binding activity of FXR agonists was determined using a LanthaScreen TR-FRET FXR Coactivator Assay Kit (Thermo Fisher Scientific, Waltham, MA, USA) as described previously [53]. TR-FRET signal was detected by an EnVision Multilabel Plate Reader (Perkin Elmer, Waltham, MA, USA).…”

“…TR-FRET signal was detected by an EnVision Multilabel Plate Reader (Perkin Elmer, Waltham, MA, USA). The EC 50 values of each compound were calculated using a probit analysis [53]. Maximum activities (%) were determined by calculating the percentage activities with respect to that of 0.5 μM of GW4064 [73].…”

“…Many of the former share isoxazole derivative and the structure modified stilbene moiety of GW4064. Among them, we focused on FXR agonists with the fused aromatic moiety (e.g., N -nonsubstituted benzimidazole) as the alternative to the stilbene while maintaining the isoxazole derivative [39], because we have previously disclosed a novel chemotype for FXR antagonists possessing an N-substituted benzimidazole scaffold and the synthetic knowledge for the building blocks containing benzimidazole [52,53,54]. In the early phase of research process of the development of FXR agonists, therefore, we selected the N -substituted benzimidazole as the alternative to the stilbene from the viewpoint of feasibility of the synthesis development and tackled using the scaffold for FXR antagonists in the development of a new chemotype for FXR agonists.…”