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Synthesis and Biological Evaluation of a Series of Bile Acid Derivatives as FXR Agonists for Treatment of NASH Hualing Xiao, Peng Li, Xiaolin Li, Haiying He, Jianhua Wang, Fengxun Guo, Jiliang Zhang, Luxia Wei, Hongmei Zhang, Yueyuan Shi, Lijuan Hou, Liang Shen, Guoping Hu, Zhengxia Chen, Chunyan Du, Shouliang Fu, Pengtao Zhang, Fei Hao, Ping Wang, Deming Xu, Wei Liang, Xin Tian, Aiming Zhang, Xingdong cheng, Ling Yang, Xiangjian Wang, Xiquan Zhang, Jian Li, and Shuhui Chen ACS Med. Chem. Lett., Just Accepted Manuscript • DOI: 10.1021/acsmedchemlett.7b00318 • Publication Date (Web): 31 Oct 2017 Downloaded from http://pubs.acs.org on November 1, 2017

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ACS Medicinal Chemistry Letters

Synthesis and Biological Evaluation of a Series of Bile Acid Derivatives as FXR Agonists for Treatment of NASH Hualing Xiao 1, Peng Li 1, Xiaolin Li 1, Haiying He 1, *, Jianhua Wang 1, Fengxun Guo 1, Jiliang Zhang1, Luxia Wei 1, Hongmei Zhang 1, Yueyuan Shi 1, Lijuan Hou 1, Liang Shen 1, Zhengxia Chen 1, Chunyan Du 1, Shouliang Fu 1, Pengtao Zhang 1, Fei Hao 1, Ping Wang 1, Deming Xu 1, Wei Liang 1, Xin Tian 2, Aiming Zhang 2, Xingdong Cheng 2, Ling Yang 2, Xiangjian Wang 2, Xiquan Zhang 2，Jian Li 1, Shuhui Chen1 1

WuXi AppTec (Shanghai) Co., Ltd, 288 FuTe Zhong Road, Shanghai 200131, P. R. China

2

Chia Tai Tianqing Pharmaceutical Group Co. Ltd., Building 9, No. 699-8, Xuanwu Road, Nanjing, Jiangsu, 210023, P. R. China KEYWORDS FXR, TGR5, Obeticholic acid, NASH

ABSTRACT: Farnesoid X receptor (FXR) has become a particularly attractive target for the discovery of drugs for the treatment of liver and metabolic diseases. Obeticholic acid (INT-747), a FXR agonist, has advanced into clinical Phase III trials in patients with non-alcoholic steatohepatitis (NASH). But adverse effects (e.g. pruritus, LDL increase) of INT-747 were observed during the clinical trial. In view of pruritus might be induced by Takeda G-protein-coupled receptor 5 (TGR5, GPBAR1), there are chances to develop FXR agonists with higher selectivity over TGR5. In this paper, novel bile acids bearing different modifications on ring A and side chain of INT-747 are reported and discussed. Our results indicated that the side chain of INT-747 is amenable to a variety of chemical modifications with good FXR potency in vitro. Especially, compound 18 not only showed promising FXR potency and excellent pharmacokinetic properties, but also proved superior pharmacological efficacy in the HFD+CCl4 model.

Introduction Farnesoid X receptor (FXR, NR1H4), mainly expressed in the liver, gastrointestinal tract, kidneys and adrenal gland1, is a member of the nuclear receptor superfamily, which was originally cloned from a rat-liver cDNA library in 19951, 2. Over recent years, FXR has greatly attracted interest of the scientific community with the aim of unraveling its physiological function and significance for disease. The main physiological role of FXR is to function as a bile acid (BA) sensor (e.g. CDCA, Scheme 1) in enterohepatic tissues. FXR positively regulates the cholesterol catabolism while feedback inhibits the BA synthesis3. FXR could also regulate plasma triglyceride (TG), energy and glucose homeostasis4. Thus, FXR is under discussion as a potential target for novel pharmacotherapies that address metabolic diseases such as NAFLD. Imbalance between the hepatic TG input and output could induce non-alcoholic fatty liver disease (NAFLD), with intrahepatic TG accumulation as its hallmark. NAFLD comprises a spectrum of hepatic histological abnormalities, ranging from simple steatosis to steatohepatitis and cirrhosis5, 6. Non-alcoholic steatohepatitis (NASH), as an extreme form of NAFLD can eventually lead to advanced fibrosis, liver cirrhosis and liver failure. However, there are no approved therapies for NASH yet7. As a promising therapeutic target, FXR has drawn numerous companies’ attention to develop novel drugs treating for liver and metabolic diseases8. Of which, Intercept’s INT-747 (synonyms obeticholic acid, Scheme 1), a

first-in-class FXR agonist as synthetic CDCA analogue, is about 100-fold more potent FXR efficacy than CDCA9 and has been approved for the treatment of primary biliary cirrhosis (PBC). In a phase II clinical trial (NCT01265498, “FLINT”) in patients with NASH, INT-747 met the primary endpoint of improving histopathological readouts [NAFLD activity score* (NAS) >= 2 pts and no worsening of fibrosis]. It has now entered clinical phase III trials for its evaluation on NASH with fibrosis in patients, and may reach the NASH market by 2018 based on prospective 72week interim analysis. Scheme 1 Chemical structures of CDCA and INT-747

The safety data in phase II clinical trials (“FLINT”) indicated that adverse drug effect, such as increased lowdensity lipoprotein cholesterol (LDL-C) and pruritus, might limit its market application. TGR5 is reported to be responsible for pruritus10, because it could activate transient receptor potential A1 (TRPA1) channel and then induce pruritus in mice. So it is presumed that improving selectivity of FXR over TGR5 might be able to ameliorate pruritus. Besides, carboxyl group of INT-747 can conjugate with taurine and glycine, these two metabolites participated in enterhepatic circulation11 and thus resulted in

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the risk of drug accumulation (50% of drug left at 90 h after single dosing12). Here we hope to develop more efficacious and selective FXR agonist over TGR5, which were derived from systematic modifications over the INT-747 skeleton.

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institution, mainly containing Intercept22, Enanta23, and our group24, focused efforts on two different areas, ring A and acidic side chain, which were classified as region I and II in Scheme 3. Scheme 3 Select modifications on INT-747.

Design Strategy In the last few years, comprehensive work9, 13-21 has been conducted with regards to the synthesis and biological evaluation of steroidal FXR agonist. Modifications were mostly based on the skeleton and side chain of CDCA (Scheme 2). These studies unveiled some valuable conclusions, such as: (a) among all 6α-alkyl CDCA analogues, INT-747 was the most potent FXR agonist. 6α-ethyl group could lie in a hydrophobic cavity inside the LBD of FXR11, which is a key structural element for FXR potency9; (b) It seems hydroxyl group on 3-position has little influence on FXR agonistic activity. Such as 3-deoxy-CDCA (1, EC50 = 1.30 μM17) showed increased activity than CDCA (EC50 = 8.66 μM17); Hydroxyl group on 7α-position was critical for the affinity to FXR15 and has to be maintained for FXR activation18. In contrast, the 7-β-epimer of CDCA, ursodeoxycholic acid (UDCA) is inactive to FXR. X-ray co-crystal structure of the FXR-LBD with INT-747 and 3-deoxyCDCA20 showed that the 7α-OH can form hydrogen bonds with Tyr366 and Ser-32911, 19. So the configuration of the hydroxyl group in position 7α is highly important. (c) The side chain of CDCA tolerated many significant structural variations (2-6, Scheme 2), including alcohol18, amino18 to amino derivatives (carbamate14 and reverse amide analogues21). Compared with CDCA, these resulting derivatives displayed comparative or even better FXR agonistic properties. 4a (EC50 = 0.41 μM) was 20 folds more potent than CDCA, docking experiments of the FXR LBD with 4a suggested that the carbonyl oxygen atom of carbamate moiety could interact with Arg32814. Compound 5 (EC50 = 0.15 μM) with 6α-ethyl group was 6 folds potent than 4b with 290% of efficacy, as a full agonist. This result further indicated that 6α-ethyl group made a great contribution to the potency and efficacy. (d) Furthermore, Daniel Merk et al have reported that bile acid derivatives with a shorter side chain were less potent than the native C24-bile acids20. Scheme 2 Reported derivatives of CDCA and INT747

Working from INT-747 as a lead while keeping the critical structural elements (6α-ethyl group and 7α-hydroxyl group) on the ring B of steroid nucleus, many research

Biological Results and Discussion INT-747 and its derivatives were synthesized and evaluated, along with CDCA as a reference control, for their ability to activate FXR using the co-activator recruitment (Alpha Screen) assay. Modifications on ring A resulted in unsatisfactory results. First, we designed and synthesized several compounds replacing 3-OH with methoxyl (7), methyl (8), hydrogen (9), difluro (10) and gemi-cyclopropane analog (11), in order to confirm impact of the hydroxyl group. Second, heterocyclic-fused A ring compound (12) was prepared, so as to confirm whether 3-hydroxyl group could be replaced by other hydrogen-bond donor. These new compounds were listed in Table 1. Elimination of the 3α-hydroxy group (9, EC50 = 0.40 μM, efficacy = 126 %) still can keep FXR potency. Replacement of 3α-OH (7, 8 and 10) all lost about 10 times potency than INT-747. Gemi-cyclopropanation (11) on the 3 position also showed decreased activity, besides it was unable to achieve full agonist efficacy (68%). This is in agreement with the experimentally determined crystal structure of INT-747 complexed with FXR11, 19, in which the 3-OH could form hydrogen bonds with Tyr-358 and His-444. Interestingly, heterocyclic-fused A ring yielded very useful information, compound 12 (EC50 = 0.30 μM, efficacy = 136 %) showed full agonist activity for FXR. This result suggested that NH of pyrazole may keep the similar hydrogen binding effect as 3-OH does. Based on this result, the hydrogen binding effect is critical for the FXR activity, since all derivatives modified around ring A resulted into a loss of 210 times potency. Compared with 4b, 5 could greatly improve the potency, especially from a partial agonist to a full agonist. We speculated that introduction of the 6α-ethyl group might be beneficial for increasing efficacy. Here, carbmate derivatives (13a-13i) were designed and synthesized based on INT-747 skeleton with an array of alternative R3groups (Table 2). It is clear that a wide variety of groups are tolerated at this position. The nucleus assay showed that all of them could keep both the potency and the efficacy on FXR. Among them, (s)-tetrahydro-3furanylcarbamate derivative 13h (EC50 = 0.09 μM, efficacy = 109 %) was confirmed as the most potent one. 6α-Ethyl group was further confirmed as a key structural element for FXR potency, because thiophene-2-methyl carbamate (13b) (EC50 = 0.23 μM, efficacy = 142 %) showed 2 times higher potency than 4a. Cell-based assay results revealed


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all of the four carbamate derivatives (13a, 13b, 13h and 13i) showed similar cell-based activity to their enzymatic activity thus indicated that carbamate analogues might be able to enter the biological membrane and interact with FXR inside the nucleus. Table 1：：Binding Potency and Efficacy of Semisynthetic ring A derivatives to FXR

crease FXR potency and efficacy. According to biochemical results, all of them showed similar and even better effect on EC50 than INT-747. In addition, all compounds showed similar efficacy from 79% to 129%, thus displaying profile of full agonists. Among these compounds, 14g, 14h and 14j with one carbon longer on side chain were about two times more potent but less efficacious than corresponding compounds 14d, 14f and 14i, respectively. Exceptionally, compound 14m with one carbon longer on side chain was less potent (EC50 = 0.37 μM) than corresponding compound 14l (EC50 = 0.08 μM). Finally, three compounds 14b (EC50 = 0.02 μM, efficacy = 109%), 14k (EC50 = 0.07 μM, efficacy = 104%) and 14l (EC50 = 0.08 μM, efficacy = 115%), which possessed better potency (3~9-fold higher potency than INT-747), were selected as candidates to be pursued further. Table 3：：Binding Potency and Efficacy of reverse amide derivatives to FXR

a Relative recruitment of the SRC1 peptide to FXR. Efficacy was calculated relative to CDCA.

Table 2：：Binding Potency and Efficacy of Carbamate derivatives to FXR

a Relative recruitment of the SRC1 peptide to FXR. Efficacy was calculated relative to CDCA as 100%.

In view of substitution of carboxylic acid group of CDCA by amino group (3) preserved both potency and efficacy, we designed and synthesized an array of reverse amides (14a-14h) and urea derivatives (14i-14m) (Table 3) by acylation of the distal C24-amino derivative with an array of electron-withdrawing R4-groups. We hoped to investigate whether introduction of 6α-ethyl group to these reverse amides and urea derivatives could also in-

a Relative recruitment of the SRC1 peptide to FXR. Efficacy calculated relative to CDCA as 100%.

Glyco-INT-747 (EC50 = 0.29 μM) and Tauro-INT-747 (EC50 = 0.23 μM) show similar potency to parent INT-747. Thus, they are considered to be active metabolites. In



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view of these two conjugates are major metabolites of INT-747 in humans, we intended to find appropriate carboxyl bioisosteres to avoid taurine and glycine metabolites. Bioisosteric derivatives (15-21) with an array of alternative R5-groups (Table 4) were synthesized. According to FXR assay result, thiol acid (16) kept activity. But amide (15), methyl ketone (17) and imidazolidine-2, 4-dione (20) led to a reduced potency. Nevertheless, two heteroaromatic compounds, H-tetrazole (21) (EC50 = 0.06 μM, efficacy = 153%) and 3-OH-isoxazole (19) (EC50 = 0.03 μM, efficacy = 121%) showed a potency 3 times and 6 times higher than INT-747, respectively. Table 4：：Binding Potency and Efficacy of carboxyl bioisosteres to FXR

a Units are μM for EC50 and % of 10 μM LCA value for efficacy. b Data represent mean values of three independent experiments.

All tested compounds showed low to moderate TGR5 potency. Of which, tetrazole derivative 21, with the best TGR5/FXR EC50 ratio of 30, was a potent and selective FXR agonist over TGR5. Four compounds (14b, 18, 19 and 21), with TGR5/FXR EC50 ratio more than 10, were subsequently chosen for further cassette PK study. PK Results and Discussion Table 6：： Liver/Plasma concentration (L/P) ratio in mice a Relative recruitment of the SRC1 peptide to FXR. Efficacy was calculated relative to CDCA as 100%.

FXR Selectivity over TGR5 Results and Discussion According to results of biological assay on FXR, five compounds (Table 5) with better FXR potency than INT747 were chosen for the biological assay on TGR5. INT747 and these five compounds were evaluated, along with LCA as a reference control, for their ability to activate TGR5 by using homogeneous time-resolved fluorescence resonance energy transfer (TR-FRET) cell-based assay. In this assay, profiles of FXR selectivity over TGR5 were investigated. Table 5: Potency and Efficacy of INT-747 Derivatives on TGR5

Note: Dosed in 0.2 mg/mL in 1%MC in water, homogenous opaque suspension with fine particles; Cassette 5 in 1 for PO, 2 mg/kg each; Male, n=3 for each time point; L/P is short for liver/plasma

14b, 18, 19 and 21 were assessed by cassette PK study in male C57BL/6 mouse via oral administration at a dose of 2 mpk each, (Table 6). The purpose was to explore Liver/Plasma concentration (L/P) ratio. Usually, higher L/P


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ratio is imperative for an ideal hepatopathy drug. According to PK results, all tested compounds showed higher L/P ratio than INT-747, especially compound 18 exhibited the highest L/P ratio at both time points (0.5 h and 3.0 h). Compound 18 was then chosen for further single PK study. According to its NDA Pharmacology Review11, it showed that after administering INT-747 to mice by oral gavage for seven days at 30 mg/kg and then fasting 12 h, only tauro-INT-747 was detected in plasma, with L/P ratio of 18. Amide bonds can be hydrolyzed by carboxylesterase, peptidase, and protease in vivo26. Compound 18, with acyl sulfamide on side chain, might be unstable and metabolized to INT-747, and then further yielded taurine and glycine metabolites. In order to prove this speculation, INT-747 and 18 were assessed in male C57BL/6 mice via oral administration at a dose of 10 mpk each. According to the PK results (Table 7), for INT-747, no glyco-INT-747 was detected, and the systemic exposure of tauro-INT-747 (AUC = 18059 nMˑh) was 25 times higher than parent INT-747 (AUC = 713 nMˑh). For 18, we assuredly detected its metabolic derivatives (INT-747, and tauro-INT-747). Table 7：：In mice Oral PK data for 18 and INT-747 PO (10 mg/kg) Compound ID

Parent & Metabolites

AUC (nM.h)

Cmax (n nM)

Tmax (h)

713

1543

0.25

Glyco-INT-747

BQL

BQL

Tauro-INT-747

18059

838

8.00

1186

610

0.5

0.5

INT-747 (Parent) INT-747

Metabolite of INT-747

18 (Parent)

nmol/kg at 3 h) as parent. Moreover, L/P ratio of metabolite INT-747 (21 at 0.5 h, 12 at 3.0 h) was also higher than INT-747 (4 at 0.5 h, 11 at 3.0 h) as parent. In view of INT747 could metabolize 10.5-fold tauro-INT-747 in mice11, we speculate that tauro-INT-747 metabolized by 18 would be higher. Compound 18, with higher total liver concentration and L/P ratio, was finally chosen and profiled in a high-fat diet plus carbon tetrachloride (HFD+CCl4) induced mouse model with the aim to demonstrate protective efficacy with respect to INT-747. Pharmacology Results and Discussion Pathogenesis of NASH is complex and there is no standard animal model for NASH research. Studies27, 28 have demonstrated that HFD+CCl4 mice model is a relatively ideal model. In several animal studies before, we found that efficacy of INT-747 at 10 mpk was not obvious. With INT-747 at 30 mpk as a positive control, compound 18 was carried out in C57BL/6J mice for its efficacy to improve liver histopathological readouts. The result during the 28 days period after administration was shown in Figure 2. INT-747 well showed positive control effect and significantly reduced liver NAS score, fibrosis and TG level. Compound 18 was evaluated at two dosages (10 mpk and 30 mpk, QD) and displayed significant dose-response relationship on improvement in liver NAS score, fibrosis and TG. Overall, the efficacy obtained for compound 18 at dosing 30 mpk was very significant, which is better than INT-747 efficacy. As one of metabolites for 18 is INT-747, the dosing of 18 might result in similar unwanted side effects by INT-747, e.g. HDL lowering, LDL increases etc.

Metabolite of 18 18

INT-747

216

446

Glyco-INT-747

BQL

BQL

Tauro-INT-747

5416

270

8.0

Note: PO PK, dosed in 1 mg/mL in 1%MC, homogenous opaque suspension; male, n=3. BQL = Below the lower limit of quantitation (LLOQ).

In order to investigate liver distribution and L/P ratio of 18 compared with INT-747, INT-747 and 18 were assessed in male C57BL/6 mice via oral administration at a dose of 10 mpk each. Table 8：：Liver/Plasma concentration (L/P) ratio for INT-747 and 18 in mice L/P ratio Test Compound ID

INT-747

Parent

Parent

Time (h)

Liver con (nmol/kg)

Plasma con. (nM)

L/P ratio

0.5

1723

478

4

3.0

111

10

11

0.5

27920

388

53

3.0

15560

298

52

0.5

2863

136

21

3.0

1486

126

12

18 INT-747 (metabolite)

Note: Dosed in 1 mg/mL in 1%MC in water, homogenous opaque suspension with fine particles, single PO, 10 mg/kg; Male, n=3 for each time point; L/P is short for liver/plasma.

According to PK results (Table 8), Liver concentration of metabolite INT-747 (2863 nmol/kg at 0.5 h, 1486 nmol/kg at 3 h) was approximately ten percent of parent 18 (27920 nmol/kg 0.5 h, 15560 nmol/kg at 3 h), and it was even higher than that of INT-747 (1723 nmol/kg, 111

Figure 1. a, b and c, liver histopathological readouts are decreased by administration of INT-747 and compound 18 to HFD+CCl4-treated mice (16 weeks old, more than 35 g). Data are the mean± S.E. of ten mice. ***p＜0.001 vs vehicle group, **p＜ 0.01 vs vehicle group, *p＜0.05 vs vehicle group, analyzed by unpaired t- test. ###p＜ 0.001 vs health control, ##p＜0.01 vs health control, #p＜0.05 vs health control, analyzed by unpaired t- test.

Conclusion The overall analysis indicated that a broad range of modulations could be tolerated on the side chains of INT747. Compound 18 in this series showed better FXR potency in vitro，excellent pharmacokinetic properties and superior pharmacological efficacy than INT-747 in the HFD+CCl4 model in vivo. Further SAR optimization on the side chain has afforded more favorable compounds. Relevant patents24 have been disclosed and details of preclinical studies will be reported in future.

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Synthetic procedures, analytical data, assay protocol are available free of charge on the ACS Publications website.

15.

AUTHOR INFORMATION

16.

Corresponding Author * E-mail: [email protected] 17.

ABBREVIATIONS LDL, low density lipoprotein; TG, total triglyceride; PK, pharmacokinetics; Cmax, peak concentration; Tmax, time to peak; QD, once a day; PO, per oral; AUC, area under curve; mpk, mg/kg.

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