Avicholic Acid: A Lead Compound from Birds on the Route to Potent TGR5 Modulators

Grounding on our former 3D QSAR studies, a knowledge-based screen of natural bile acids from diverse animal species has led to the identification of avicholic acid as a selective but weak TGR5 agonist. Chemical modifications of this compound resulted in the disclosure of 6α-ethyl-16-<i>epi</i>-avicholic acid that shows enhanced potency at TGR5 and FXR receptors. The synthesis, biological appraisals, and structure–activity relationships of this series of compounds are herein described. Moreover, a thorough physicochemical characterization of 6α-ethyl-16-<i>epi</i>-avicholic acid as compared to naturally occurring bile acids is reported and discussed

Effect of curcuma extract on 5-HT biphasic activity (contraction and then relaxation) in mouse distal colon.

<p>Mouse distal colon smooth muscle has been exposed to 5-HT (50 µM) before (control) and after exposure to 0.1 mg/ml curcuma extract for 30 min.. Data are mean ± SEM values (<i>n</i> = 3-5). Error bars are not shown where they are covered by the point itself.</p

Spasmolitic effect of curcuma extract on K⁺ (80 mM) induced contraction on isolated ileum (dark blu) and on isolated distal colon (light blu).

<p>Dose-response curves of curcuma extract. Data are means ± SEM values (<i>n</i> = 3-5). Error bars are not shown where they are covered by the point itself.</p

Discovery of 3α,7α,11β-Trihydroxy-6α-ethyl-5β-cholan-24-oic Acid (TC-100), a Novel Bile Acid as Potent and Highly Selective FXR Agonist for Enterohepatic Disorders

As a continuation of previous efforts in mapping functional hot spots on the bile acid scaffold, we here demonstrate that the introduction of a hydroxy group at the C11β position affords high selectivity for FXR. In particular, the synthesis and FXR/TGR5 activity of novel bile acids bearing different hydroxylation patterns at the C ring are reported and discussed from a structure–activity standpoint. The results obtained led us to discover the first bile acid derivative endowed with high potency and selectivity at the FXR receptor, 3α,7α,11β-trihydroxy-6α-ethyl-5β-cholan-24-oic acid (TC-100, <b>7</b>) which also shows a remarkable physicochemical and pharmacological profile. Compound <b>7</b> combines the excellent physicochemical properties of hydrophilic bile acids such as ursodeoxycholic acid, with the distinct ability to specifically bind and regulate FXR activity in vivo, thus providing a bona fide novel therapeutic agent to treat enterohepatic disorders such as cholestasis, NASH, and inflammatory bowel disease

Effect of curcuma on histamine-induced contraction in isolated mice ileum.

<p>(A) Cumulative concentration-response curves were obtained before and after exposure to curcuma extract for 30 minutes. Data are mean ± SEM values (<i>n</i> = 5-6). (B) Time course of curcuma extract effect on histamine-induced contraction in isolated mice ileum (100%). Cumulative concentration-response curves were obtained before and after exposure to Curcuma extract (0.025 mg/ml) for 5, 15, 30, and 45 minutes. Data are mean ± SEM values (<i>n</i> = 4-7). (C) Time course of effect of curcuma-extract (0.025 mg/ml) on histamine-induced contraction in isolated mice ileum. Cumulative concentration-response curves were obtained before and after exposure to curcuma extract (0.025 mg/ml) and following washing for 5, 30, and 60 minutes. Data are mean ± SEM values (<i>n</i> = 3-5). Error bars are not shown where they are covered by the point itself. </p

Basal contractile activity: effect of Curcuma extract 1 mg/ml.

<p>(A,B) baseline gastric smooth muscle phasic contractions before (A) and after curcuma extract addition (B). (C,D): races of baseline trachea smooth muscle phasic contractions before (C) and after curcuma administration (D ). (E,F): traces of baseline smooth muscle bladder phasic contractions before (E) and after curcuma administration (F). X axis (g) and Y axis (h). (G): spontaneous phasic contractions frequency in gastric fundus, trachea, bladder strips (mean ± SEM) (C): Spontaneous phasic contractions amplitude in gastric fundus, trachea, bladder strips (mean ± SEM). In all cases Curcuma vs controls <i>P</i> > 0.05.</p