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    • The PK profile and tissue distribution of which has

    2021-09-26

    The PK profile and tissue distribution of 30, which has biological properties almost equivalent to those of 12, were examined in comparison with 12. Analog 30 was evaluated in a 6 h rat PK study at an intravenous (iv) dosing of 1 mg/kg in 10% 2-hydroxypropyl--cyclodextrin (HP-β-CD) (Table 2) and an oral (po) dosing of 30 mg/kg in 40% HP-β-CD compared with parent analog 12. (Table 3 and Fig. S5) Both analogs exhibited moderate effect after the iv injection in plasma (AUC0-360 = 10.90 ± 1.57 and 17.53 ± 1.58 mg·min/mL), modest half-lives and high volume of distribution. The low urinary IPA-3 ratio of 12 and 30 implies the possibility of some metabolite breakdown products. No significant differences were found between both compounds upon iv administration. In contrast, the PK profiles of 30 in po administration (Table 3) were obviously superior to those of 12. (e.g., F = 17.99 ± 3.52 and 2.76 ± 0.31, respectively) The plasma and tissue concentrations of 12 and 30 at 6 h after po administration were examined as shown in Fig. 5. Treatment with 30 resulted in a higher concentration in the plasma and the target tissues (liver and ileum30, 31) of FXR than that with 12. The concentrations of 30 in the liver and ileum were 15 and 13-fold higher, respectively, than that found in plasma. Thus, we concluded that our data provides a more comprehensive understanding of the SAR of 12, one that led to the discovery of 30 with better PK profiles and distribution in liver and ileum while retaining high potency as a specific FXR antagonist.
    Conclusion We developed analog 30, which improved the in vivo PK profile and the distribution toward the target tissues (liver and ileum30, 31) of 12 without a decline in the in vitro activity by modifying region G. Modification in region G is, therefore, one of the structural parameters for modulating PK parameters and tissue distribution of our chemotype for FXR antagonists. Additionally, further studies on this region could lead to an enhancement of its physicochemical property. Notably, the distribution of 30 (1536.95 ± 440.65 ng/g liver and 1366.04 ± 439.65 ng/g ileum) in liver and ileum was approximately 6.8- and 10-fold higher than that of 12 (225.48 ± 135.69 ng/g liver and 135.02 ± 104.57 ng/g ileum), respectively. On the relationship between FXR and the intestine, it has been recently reported that blunting FXR activity in the intestine in non-alcoholic fatty liver disease (NAFLD),30, 31 type 2 diabetes (DA) and obesity would be a more viable approach in targeting these diseases. Furthermore, additional investigations would dwell on an exploration of the potential of the intestinal FXR in rodents and/or primates. To that end, the selective inhibition of FXR in the intestine using 30, would be preferable and it should serve as a potential candidate for in vivo evaluation in future investigations to determine how FXR is intimately involved in NAFLD, DA and obesity.
    Experimentals
    Acknowledgements
    Introduction Farnesoid X receptor (FXR) belongs to a member of nuclear receptor superfamily, and mainly expresses in liver, kidney, intestine and adrenal gland [[1], [2], [3]]. FXR is activated by bile acid to regulate the target genes responsible for bile acid metabolism [4], and tightly linked to liver protection from harmful effects of bile acid overload. For example, FXR agonist obeticholic acid (Ocaliva) can treat primary biliary cholangitis [5], and other agonists like GS-9674 and LN452 are being developed to treat nonalcoholic steatohepatitis (in phase 2 clinical study) [6]. In fact, FXR has become a promising target for designing drug lead compound against metabolic disorders [7]. Type 2 diabetes mellitus (T2DM) is a progressively metabolic disease, characterized by abnormal glucose and lipid metabolism [8,9]. Pathologically, increased hepatic gluconeogenesis is largely responsible for hyperglycemia in T2DM patients [10,11], and hepatic gluconeogenesis inhibition is a potently therapeutic strategy for T2DM, as indicated by the first-line clinical anti-diabetes drugs like metformin and pioglitazone [[12], [13], [14]].