Semisynthetic bile acid FXR and TGR5 agonists: Physicochemical properties, pharmacokinetics, and metabolism in the rats

Journal of Pharmacology and Experimental Therapeutics

Volumn 350, Issue 1, 2014, Pages 56-68

  Roda, Aldo ^a   Pellicciari, Roberto ^b,c   Gioiello, Antimo ^b   Neri, Flavia ^a   Camborata, Cecilia ^a   Passeri, Daniela ^c   De Franco, Francesca ^c   Spinozzi, Silvia ^a   Colliva, Carolina ^c   Adorini, Luciano ^c   Montagnani, Marco ^a   Aldini, Rita ^a,d  

^a UNIVERSITY OF BOLOGNA   (Italy)

^b UNIVERSITY OF PERUGIA   (Italy)

^c Dipartimento di Scienze Mediche e Chirurgiche Alma Mater Studiorum University of Bologna ^*

^d INTERCEPT PHARMACEUTICALS   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

6 ALPHA ETHYL 3 ALPHA,7 ALPHA DIHYDROXY 24 NOR 5 BETA CHOLAN 23 SULFATE; 6 ALPHA ETHYL 3 ALPHA,7 ALPHA DIHYDROXY 5 BETA CHOLAN 24 OIC ACID; 6ALPHA ETHYL 23 METHYL 3 ALPHA,7 ALPHA,12 ALPHA TRIHYDROXY 5 BETA CHOLAN 24 OIC ACID; BILE ACID; CHENODEOXYCHOLIC ACID; CHOLIC ACID; FARNESOID X RECEPTOR; G PROTEIN COUPLED RECEPTOR; INT 767; INT 777; OBETICHOLIC ACID; TAURINE; TAUROCHENODEXYCHOLIC ACID; UNCLASSIFIED DRUG;

ANIMAL MODEL; AREA UNDER THE CURVE; ARTICLE; BILE DUCT FISTULA; BILE FLOW; BILE SECRETION; CONTROLLED STUDY; CRITICAL MICELLE CONCENTRATION; DISSOCIATION CONSTANT; DRUG ABSORPTION; DRUG BLOOD LEVEL; DRUG CLEARANCE; DRUG CONJUGATION; DRUG METABOLISM; DRUG STRUCTURE; ELECTROSPRAY MASS SPECTROMETRY; ENZYME SPECIFICITY; FECES CULTURE; HIGH PERFORMANCE LIQUID CHROMATOGRAPHY; IN VIVO STUDY; INTESTINE MOTILITY; LIPOPHILICITY; NONHUMAN; PARTITION COEFFICIENT; PHYSICAL CHEMISTRY; PRIORITY JOURNAL; PROTEIN BINDING; RAT; SURFACE TENSION;

ANIMALS; BACTERIA; BILE; BILE ACIDS AND SALTS; HUMANS; LIVER; PHYSICOCHEMICAL PROCESSES; RATS; RECEPTORS, CYTOPLASMIC AND NUCLEAR; RECEPTORS, G-PROTEIN-COUPLED;

EID: 84903550751     PISSN: 00223565     EISSN: 15210103     Source Type: Journal    
DOI: 10.1124/jpet.114.214650     Document Type: Article

References (59)

1. Adorini L, Pruzanski M, and Shapiro D (2012) Farnesoid X receptor targeting to treat nonalcoholic steatohepatitis. Drug Discov Today 17:988-997.
2. Aldini R, Roda A, Montagnani M, Cerrè C, Pellicciari R, and Roda E (1996) Relationship between structure and intestinal absorption of bile acids with a steroid or side-chain modification. Steroids 61:590-597. (Pubitemid 26375153
3. Baghdasaryan A, Claudel T, Gumhold J, Silbert D, Adorini L, Roda A, Vecchiotti S, Gonzalez FJ, Schoonjans K, and Strazzabosco M, et al. (2011) Dual farnesoid X receptor/TGR5 agonist INT-767 reduces liver injury in the Mdr2-/-(Abcb4-/-) mouse cholangiopathy model by promoting biliary HCO-3 output. Hepatology 54: 1303-1312.
4. Boyer JL, Trauner M, Mennone A, Soroka CJ, Cai SY, Moustafa T, Zollner G, Lee JY, and Ballatori N (2006) Upregulation of a basolateral FXR-dependent bile acid efflux transporter OSTalpha-OSTbeta in cholestasis in humans and rodents. Am J Physiol Gastrointest Liver Physiol 290:G1124-G1130. (Pubitemid 43788293
5. Claudel T, Sturm E, Duez H, Torra IP, Sirvent A, Kosykh V, Fruchart JC, Dallongeville J, Hum DW, and Kuipers F, et al. (2002) Bile acid-activated nuclear receptor FXR suppresses apolipoprotein A-I transcription via a negative FXR response element. J Clin Invest 109:961-971. (Pubitemid 34275117
6. De Fabiani E, Mitro N, Gilardi F, Caruso D, Galli G, and Crestani M (2003) Coordinated control of cholesterol catabolism to bile acids and of gluconeogenesis via a novel mechanism of transcription regulation linked to the fasted-to-fed cycle. J Biol Chem 278:39124-39132. (Pubitemid 37221815
7. Düfer M, Hörth K, Krippeit-Drews P, and Drews G (2012) The significance of the nuclear farnesoid X receptor (FXR) in β cell function. Islets 4:333-338.
8. Duran-Sandoval D, Mautino G, Martin G, Percevault F, Barbier O, Fruchart JC, Kuipers F, and Staels B (2004) Glucose regulates the expression of the farnesoid X receptor in liver. Diabetes 53:890-898. (Pubitemid 38436600
9. Gadaleta RM1, van Erpecum KJ, Oldenburg B, Willemsen EC, Renooij W, Murzilli S, Klomp LW, Siersema PD, Schipper ME, and Danese S, et al. (2011) Farnesoid X receptor activation inhibits inflammation and preserves the intestinal barrier in inflammatory bowel disease. Gut 60:463-472.
10. Gioiello A, Macchiarulo A, Carotti A, Filipponi P, Costantino G, Rizzo G, Adorini L, and Pellicciari R (2011) Extending SAR of bile acids as FXR ligands: discovery of 23-N-(carbocinnamyloxy)-3α,7α-dihydroxy-6α- ethyl-24-nor-5β-cholan-23-amine. Bioorg Med Chem 19:2650-2658.
11. Gioiello A, Rosatelli E, Nuti R, Macchiarulo A, and Pellicciari R (2012) Patented TGR5 modulators: a review (2006-present). Expert Opin Ther Pat 22:1399-1414.
12. Gurantz D and Hofmann AF (1984) Influence of bile acid structure on bile flow and biliary lipid secretion in the hamster. Am J Physiol 247:G736-G748.
13. Hofmann AF and Roda A (1984) Physicochemical properties of bile acids and their relationship to biological properties: an overview of the problem. J Lipid Res 25: 1477-1489. (Pubitemid 15169464
14. Houten SM and Auwerx J (2004) The enterohepatic nuclear receptors are major regulators of the enterohepatic circulation of bile salts. Ann Med 36:482-491. (Pubitemid 39490958
15. Inagaki T, Moschetta A, Lee YK, Peng L, Zhao G, Downes M, Yu RT, Shelton JM, Richardson JA, and Repa JJ, et al. (2006) Regulation of antibacterial defense in the small intestine by the nuclear bile acid receptor. Proc Natl Acad Sci USA 103: 3920-3925. (Pubitemid 43376656
16. Kalaany NY and Mangelsdorf DJ (2006) LXRS and FXR: the yin and yang of cholesterol and fat metabolism. Annu Rev Physiol 68:159-191.
17. Kast HR, Nguyen CM, Sinal CJ, Jones SA, Laffitte BA, Reue K, Gonzalez FJ, Willson TM, and Edwards PA (2001) Farnesoid X-activated receptor induces apolipoprotein C-II transcription: a molecular mechanism linking plasma triglyceride levels to bile acids. Mol Endocrinol 15:1720-1728. (Pubitemid 32939302
18. Kawamata Y, Fujii R, Hosoya M, Harada M, Yoshida H, Miwa M, Fukusumi S, Habata Y, Itoh T, and Shintani Y, et al. (2003) A G protein-coupled receptor responsive to bile acids. J Biol Chem 278:9435-9440. (Pubitemid 36800434
19. Keitel V, Cupisti K, Ullmer C, Knoefel WT, Kubitz R, and Häussinger D (2009) The membrane-bound bile acid receptor TGR5 is localized in the epithelium of human gallbladders. Hepatology 50:861-870.
20. Keitel V, Donner M, Winandy S, Kubitz R, and Häussinger D (2008) Expression and function of the bile acid receptor TGR5 in Kupffer cells. Biochem Biophys Res Commun 372:78-84. (Pubitemid 351778164
21. Keitel V, Reinehr R, Gatsios P, Rupprecht C, Görg B, Selbach O, Häussinger D, and Kubitz R (2007) The G-protein coupled bile salt receptor TGR5 is expressed in liver sinusoidal endothelial cells. Hepatology 45:695-704. (Pubitemid 46450621
22. Kumar DP, Rajagopal S, Mahavadi S, Mirshahi F, Grider JR, Murthy KS, and Sanyal AJ (2012) Activation of transmembrane bile acid receptor TGR5 stimulates insulin secretion in pancreatic β cells. Biochem Biophys Res Commun 427:600-605.
23. Lefebvre P, Cariou B, Lien F, Kuipers F, and Staels B (2009) Role of bile acids and bile acid receptors in metabolic regulation. Physiol Rev 89:147-191.
24. Mak PA, Kast-Woelbern HR, Anisfeld AM, and Edwards PA (2002) Identification of PLTP as an LXR target gene and apoE as an FXR target gene reveals overlapping targets for the two nuclear receptors. J Lipid Res 43:2037-2041. (Pubitemid 35471069
25. Makishima M, Okamoto AY, Repa JJ, Tu H, Learned RM, Luk A, Hull MV, Lustig KD, Mangelsdorf DJ, and Shan B (1999) Identification of a nuclear receptor for bile acids. Science 284:1362-1365. (Pubitemid 29289663
26. Maneschi E, Vignozzi L, Morelli A, Mello T, Filippi S, Cellai I, Comeglio P, Sarchielli E, Calcagno A, and Mazzanti B, et al. (2013) FXR activation normalizes insulin sensitivity in visceral preadipocytes of a rabbit model of MetS. J Endocrinol 218: 215-231.
27. Maruyama T, Miyamoto Y, Nakamura T, Tamai Y, Okada H, Sugiyama E, Nakamura T, Itadani H, and Tanaka K (2002) Identification of membrane-type receptor for bile acids (M-BAR). Biochem Biophys Res Commun 298:714-719. (Pubitemid 35356798
28. McMahan RH, Wang XX, Cheng LL, Krisko T, Smith M, El Kasmi K, Pruzanski M, Adorini L, Golden-Mason L, and Levi M, et al. (2013) Bile acid receptor activation modulates hepatic monocyte activity and improves nonalcoholic fatty liver disease. J Biol Chem 288:11761-11770.
29. Mudaliar S, Henry RR, Sanyal AJ, Morrow L, Marschall HU, Kipnes M, Adorini L, Sciacca CI, Clopton P, and Castelloe E, et al. (2013) Efficacy and safety of the farnesoid X receptor agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease. Gastroenterology 145:574-582, e1.
30. Naiki Y, Sorrentino R, Wong MH, Michelsen KS, Shimada K, Chen S, Yilmaz A, Slepenkin A, Schröder NW, and Crother TR, et al. (2008) TLR/MyD88 and liver X receptor alpha signaling pathways reciprocally control Chlamydia pneumoniaeinduced acceleration of atherosclerosis. J Immunol 181:7176-7185.
31. Parks DJ, Blanchard SG, Bledsoe RK, Chandra G, Consler TG, Kliewer SA, Stimmel JB, Willson TM, Zavacki AM, and Moore DD, et al. (1999) Bile acids: natural ligands for an orphan nuclear receptor. Science 284:1365-1368. (Pubitemid 29289664
32. Pellicciari R, Costantino G, Camaioni E, Sadeghpour BM, Entrena A, Willson TM, Fiorucci S, Clerici C, and Gioiello A (2004) Bile acid derivatives as ligands of the farnesoid X receptor. Synthesis, evaluation, and structure-activity relationship of a series of body and side chain modified analogues of chenodeoxycholic acid. J Med Chem 47:4559-4569.
33. Pellicciari R, Fiorucci S, Camaioni E, Clerici C, Costantino G, Maloney PR, Morelli A, Parks DJ, and Willson TM (2002) 6alpha-ethyl-chenodeoxycholic acid (6-ECDCA), a potent and selective FXR agonist endowed with anticholestatic activity. J Med Chem 45:3569-3572. (Pubitemid 34856095
34. Pellicciari R, Gioiello A, Macchiarulo A, Thomas C, Rosatelli E, Natalini B, Sardella R, Pruzanski M, Roda A, and Pastorini E, et al. (2009) Discovery of 6alpha-ethyl-23 (S)-methylcholic acid (S-EMCA, INT-777) as a potent and selective agonist for the TGR5 receptor, a novel target for diabesity. J Med Chem 52:7958-7961.
35. Pellicciari R, Gioiello A, Sabbatini P, Venturoni F, Nuti R, Colliva C, Rizzo G, Adorini L, Pruzanski M, and Roda A, et al. (2012) Avicholic acid: a lead compound from birds on the route to potent TGR5 modulators. ACS Med. Chem. Lett. 3:273-277.
36. Pols TW, Nomura M, Harach T, Lo Sasso G, Oosterveer MH, Thomas C, Rizzo G, Gioiello A, Adorini L, and Pellicciari R, et al. (2011) TGR5 activation inhibits atherosclerosis by reducing macrophage inflammation and lipid loading. Cell Metab 14:747-757.
37. Poole DP, Godfrey C, Cattaruzza F, Cottrell GS, Kirkland JG, Pelayo JC, Bunnett NW, and Corvera CU (2010) Expression and function of the bile acid receptor GpBAR1 (TGR5) in the murine enteric nervous system. Neurogastroenterol Motil 22:814-825, e227-e228.
38. Porez G, Prawitt J, Gross B, and Staels B (2012) Bile acid receptors as targets for the treatment of dyslipidemia and cardiovascular disease. J Lipid Res 53: 1723-1737.
39. Rizzo G, Passeri D, De Franco F, Ciaccioli G, Donadio L, Rizzo G, Orlandi S, Sadeghpour B, Wang XX, and Jiang T, et al. (2010) Functional characterization of the semisynthetic bile acid derivative INT-767, a dual farnesoid X receptor and TGR5 agonist. Mol Pharmacol 78:617-630.
40. Roda A, Aldini R, Grigolo B, Simoni P, Roda E, Pellicciari R, Lenzi PL, and Natalini B (1988) 23-Methyl-3 alpha,7 beta-dihydroxy-5 beta-cholan-24-oic acid: doseresponse study of biliary secretion in rat. Hepatology 8:1571-1576. (Pubitemid 19021890
41. Roda A, Cappelleri G, Aldini R, Roda E, and Barbara L (1982) Quantitative aspects of the interaction of bile acids with human serum albumin. J Lipid Res 23:490-495. (Pubitemid 12094762
42. Roda A and Fini A (1984) Effect of nuclear hydroxy substituents on aqueous solubility and acidic strength of bile acids. Hepatology 4(5, Suppl)72S-76S.
43. Roda A, Grigolo B, Aldini R, Simoni P, Pellicciari R, Natalini B, and Balducci R (1987) Bile acids with a cyclopropyl-containing side chain. IV. Physicochemical and biological properties of the four diastereoisomers of 3 alpha,7 betadihydroxy-22,23-methylene-5 beta-cholan-24-oic acid. J Lipid Res 28: 1384-1397. (Pubitemid 18025872
44. Roda A, Hofmann AF, and Mysels KJ (1983) The influence of bile salt structure on self-association in aqueous solutions. J Biol Chem 258:6362-6370. (Pubitemid 13106811
45. Roda A, Minutello A, Angellotti MA, and Fini A (1990) Bile acid structure-activity relationship: evaluation of bile acid lipophilicity using 1-octanol/water partition coefficient and reverse phase HPLC. J Lipid Res 31:1433-1443. (Pubitemid 20261907
46. Roda A, Pellicciari R, Cerrè C, Polimeni C, Sadeghpour B, Marinozzi M, Forti GC, and Sapigni E (1994) New 6-substituted bile acids: physico-chemical and biological properties of 6 alpha-methyl ursodeoxycholic acid and 6 alpha-methyl-7-epicholic acid. J Lipid Res 35:2268-2279.
47. Schaap FG, Trauner M, and Jansen PLM (2014) Bile acid receptors as targets for drug development. Nat Rev Gastroenterol Hepatol 11:55-67.
48. Schmidt WE, Siegel EG, and Creutzfeldt W (1985) Glucagon-like peptide-1 but not glucagon-like peptide-2 stimulates insulin release from isolated rat pancreatic islets. Diabetologia 28:704-707. (Pubitemid 16226411
49. Sinal CJ, Tohkin M, Miyata M, Ward JM, Lambert G, and Gonzalez FJ (2000) Targeted disruption of the nuclear receptor FXR/BAR impairs bile acid and lipid homeostasis. Cell 102:731-744.
50. Stayrook KR, Bramlett KS, Savkur RS, Ficorilli J, Cook T, Christe ME, Michael LF, and Burris TP (2005) Regulation of carbohydrate metabolism by the farnesoid X receptor. Endocrinology 146:984-991. (Pubitemid 40289284
51. Stroeve JH, Brufau G, Stellaard F, Gonzalez FJ, Staels B, and Kuipers F (2010) Intestinal FXR-mediated FGF15 production contributes to diurnal control of hepatic bile acid synthesis in mice. Lab Invest 90:1457-1467.
52. Thomas C, Auwerx J, and Schoonjans K (2008) Bile acids and the membrane bile acid receptor TGR5-connecting nutrition and metabolism. Thyroid 18: 167-174. (Pubitemid 351271532
53. Thomas C, Gioiello A, Noriega L, Strehle A, Oury J, Rizzo G, Macchiarulo A, Yamamoto H, Mataki C, and Pruzanski M, et al. (2009) TGR5-mediated bile acid sensing controls glucose homeostasis. Cell Metab 10:167-177.
54. Tu H, Okamoto AY, and Shan B (2000) FXR, a bile acid receptor and biological sensor. Trends Cardiovasc Med 10:30-35. (Pubitemid 32013925
55. Une M, Cohen BI, and Mosbach EH (1984) New bile acid analogs: 3 alpha, 7 alphadihydroxy-7 beta-methyl-5 beta-cholanoic acid, 3 alpha, 7 beta-dihydroxy-7 alphamethyl-5 beta-cholanoic acid, and 3 alpha-hydroxy-7 xi-methyl-5 beta-cholanoic acid. J Lipid Res 25:407-410.
56. Urizar NL, Dowhan DH, and Moore DD (2000) The farnesoid X-activated receptor mediates bile acid activation of phospholipid transfer protein gene expression. J Biol Chem 275:39313-39317. (Pubitemid 32058952
57. Watanabe M, Houten SM, Mataki C, Christoffolete MA, Kim BW, Sato H, Messaddeq N, Harney JW, Ezaki O, and Kodama T, et al. (2006) Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation. Nature 439:484-489. (Pubitemid 43152840
58. Yoshii M, Mosbach EH, Schteingart CD, Hagey LR, Hofmann AF, Cohen BI, and McSherry CK (1991) Chemical synthesis and hepatic biotransformation of 3 alpha,7 alpha-dihydroxy-7 beta-methyl-24-nor-5 beta-cholan-23-oic acid, a 7-methyl derivative of norchenodeoxycholic acid: studies in the hamster. J Lipid Res 32: 1729-1740.
59. Zollner G, Marschall HU, Wagner M, and Trauner M (2006) Role of nuclear receptors in the adaptive response to bile acids and cholestasis: pathogenetic and therapeutic considerations. Mol Pharm 3:231-251. (Pubitemid 44021431)