Improvement of physiochemical properties of the tetrahydroazepinoindole series of farnesoid X receptor (FXR) agonists: Beneficial modulation of lipids in primates

Journal of Medicinal Chemistry

Volumn 53, Issue 4, 2010, Pages 1774-1787

  Lundquist IV, Joseph T ^a   Harnish, Douglas C ^a   Kim, Callain Y ^a   Mehlmann, John F ^a   Unwalla, Rayomand J ^a   Phipps, Kristin M ^a   Crawley, Matthew L ^a   Commons, Thomas ^a   Green, Daniel M ^a   Xu, Weixin ^a   Hum, Wah Tung ^a   Eta, Julius E ^a   Feingold, Irene ^a   Patel, Vikram ^a   Evans, Mark J ^a   Lai, Kehdih ^a   Borges Marcucci, Lisa ^a   Mahaney, Paige E ^a   Wrobel, Jay E ^a  

^a PFIZER INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

8 FLUORO 1,1 DIMETHYL 3 [4 (2 MORPHOLIN 4 YLETHOXY) BENZOYL] 1,2,36 TETRAHYDROAZEPINO[4,5 B]INSOLE 5 CARBOXYLATE; 8 FLUORO 1,1 DIMETHYL 3 [4 (3 MORPHOLIN 4 YLPROPOXY) BENZOYL] 1,2,36 TETRAHYDROAZEPINO[4,5 B]INSOLE 5 CARBOXYLATE; FARNESOID X RECEPTOR; FARNESOID X RECEPTOR AGONIST; INDOLE DERIVATIVE; LOW DENSITY LIPOPROTEIN; LOW DENSITY LIPOPROTEIN CHOLESTEROL; TETRAHYDROAZEPINOINDOLE; TRIACYLGLYCEROL; UNCLASSIFIED DRUG; VERY LOW DENSITY LIPOPROTEIN CHOLESTEROL;

ANIMAL EXPERIMENT; ARTICLE; CONTROLLED STUDY; CRYSTAL STRUCTURE; DYSLIPIDEMIA; FEMALE; MOUSE; NONHUMAN; PRIMATE; RHESUS MONKEY;

ANIMALS; ANTILIPEMIC AGENTS; AZEPINES; BIOLOGICAL AVAILABILITY; CELL LINE; CHOLESTEROL, LDL; FEMALE; HUMANS; INDOLES; MACACA MULATTA; MALE; MICE; MICE, KNOCKOUT; MICROSOMES, LIVER; MODELS, MOLECULAR; RATS; RATS, SPRAGUE-DAWLEY; RECEPTORS, CYTOPLASMIC AND NUCLEAR; RECEPTORS, LDL; SOLUBILITY; STRUCTURE-ACTIVITY RELATIONSHIP; TRIGLYCERIDES;

EID: 77649229482     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm901650u     Document Type: Article

References (27)

1. (a) Forman, B. M.; Goode, E.; Chen, J.; Oro, A. E.; Bradley, D. J.; Perlmann, T.; Noonan, D. J.; Burka, L. T.; McMorris, T.; Lamph, W. W.; Evans, E. M.; Weinberger, C. Identification of a nuclear receptor that is activated by farnesol metabolites. Cell 1995, 81, 687-693.
2. (b) Zhang, Y.; Kast-Woelbern, H. R.; Edwards, P. A. Natural structural variants of the nuclear receptor farnesoid X receptor affect transcriptional activation. J. Biol. Chem. 2003, 278, 101-110.
3. (c) Otte, K.; Kranz, H.; Kober, I.; Thompson, P.; Hoefer, M.; Haubold, B.; Remmel, B.;Voss, H.; Kaiser, C.; Albers, M.; Cheruvallath, Z.; Jackson, D.; Casari, G.; Koegl, M.; Paabo, S.; Mous, J.; Kremoser, C.; Deuschle, U. Identification of farnesoid X receptor β as a novel mammalian nuclear receptor sensing lanosterol. Mol. Cell. Biol. 2003, 23, 864-872.
4. (a) Makishima, M.; Okamoto, A. Y.; Repa, J. J.; Tu, H.; Learned, R. M.; Luk, A.; Hull, M. V.; Lustig, K. D.; Mangelsdorf, D. J.; Shan, B. Identification of a nuclear receptor for bile acids. Science 1999, 284, 1362-1365. (Pubitemid 29289663)
5. (b) Parks, D. J.; Blanchard, S. G.; Bledsoe, R. K.; Chandra, G.; Consler, T. G.; Kliewer, S. A.; Stimmel, J. B.; Willson, T. M.; Zavacki, A. M.; Moore, D. D.; Lehmann, J. M. Bile acids: natural ligands for an orphan nuclear receptor. Science 1999, 284, 1365-1368. (Pubitemid 29289664)
6. (a) Pellicciari, R.; Costantino, G.; Fiorucci, S. Farnesoid X receptor: From structure to potential clinical applications. J. Med. Chem. 2005, 48, 5383-5403.
7. (b) Rizzo, G.; Renga, B.; Antonelli, E.; Passeri, D.; Pellicciari, R.; Fiorucci, S. The methyl transferase PRMT1 functions as co-activator of farnesoid X receptor (FXR)/9-cis retinoid X receptor and regulates transcription of FXR responsive genes. Mol. Pharmacol. 2005, 68, 551-555.
8. Sinal, C. J.; Tohkin, M.; Miyata, M.; Ward, J. M.; Lambert, G.; Gonzalez, F. J. Targeted disruption of the nuclear receptor FXR/BAR impairs bile acid and lipid homeostasis. Cell 2000, 102, 731-744.
9. Claudel, T.; Staels, B.t; Kuipers, F. The farnesoid X receptor: A molecular link between bile acid and lipid and glucose metabolism. Arterioscler. Thromb. Vasc. Biol. 2005, 25, 2020-2030.
10. Hirokane, H.; Nakahara, M.; Tachibana, S.; Shimizu, M.; Sato, R. Bile acid reduces the secretion of VLDL by repressing microsomal triglyceride transfer protein gene expression mediated by hepatocyte nuclear factor-4. J. Biol. Chem. 2004, 279, 45685-45692.
11. Bell, G. D.; Lewis, B.; Petrie, A.; Dowling, R. H. Serum lipids in cholelithiasis: Effect of chenodeoxycholic acid therapy. Br. Med. J. 1973, 3, 520-523.
12. Angelin, B.; Hershon, K. S.; Brunzell, J. D. Bile acid metabolism in hereditary forms of hypertriglyceridemia: Evidence for an increased synthesis rate in monogenic familial hypertriglyceridemia. Proc. Natl. Acad. Sci. U. S. A. 1987, 84, 5434-5438.
13. Angelin, B.; Einarsson, K.; Hellstrom, K.; Leijd, B. Effects of chenodeoxycholic acid on the metabolism of endogenous triglyceride and hyperlipoproteinemia. J. Lipid Res. 1978, 19, 1017-1024. (Pubitemid 9059813)
14. Chawla, A.; Repa, J. J.; Evans, R. M.; Mangelsdorf, D. J. Nuclear receptors and lipid physiology: Opening the X-files. Science 2001, 294, 1866-1870. (Pubitemid 33101573)
15. Yu, L.; Gupta, S.; Xu, F.; Liverman, A. D. B.; Moschetta, A.; Mangelsdorf, D. J.; Repa, J. J.; Hobbs, H. H.; Cohen, J. C. Expression of ABCG5 and ABCG8 is required for regulation of biliary cholesterol secretion. J. Biol. Chem. 2005, 280, 8742-8747.
16. Evans, M. J.; Mahaney, P. E.; Borges-Marcucci, L.; Lai, K.-D.; Wang, S.; Krueger, J. A.; Gardell, S. J.; Huard, C.; Martinez, R.; Vlasuk, G. P.; Harnish, D. C. A synthetic farnesoid X receptor (FXR) agonist promotes cholesterol lowering in models of dyslipidemia. Am. J. Physiol. Gastrointest. Liver Physiol. 2009, 296, G543-G552.
17. Maloney, P. R.; Parks, D. J.; Haffner, C. D.; Fivush, A. M.; Chandra, G.; Plunket, K. D.; Creech, K. L.; Moore, L. B.; Wilson, J. G.; Lewis, M. C.; Jones, S. A.; Willson, T. M. Identification of a chemical tool for the orphan nuclear receptor FXR. J. Med. Chem. 2000, 43, 2971-2974.
18. Nicolaou, K. C.; Evans, R. M.; Roecker, A. J.; Hughes, R.; Downes, M.; Pfefferkorn, J. A. Discovery and optimization of non-steroidal FXR agonists from natural product-like libraries. Org. Biomol. Chem. 2003, 1, 908-920.
19. Pellicciari, R.; Fiorucci, S.; Camaioni, E.; Clerici, C.; Costantino, G.; Maloney, P. R.; Morelli, A.; Parks, D. J.; Willson, T. M. 6-Alpha-ethyl- chenodeoxycholic acid (6-ECDCA), a potent and selective FXR agonist endowed with anticholestatic activity. J. Med. Chem. 2002, 45, 3569-3572.
20. Flatt, B.; Martin, R.; Wang, T.-L.; Mahaney, P.; Murphy, B.; Gu, X.-H.; Foster, P.; Li, J.; Pircher, P.; Petrowski, M.; Schulman, I.; Westin, S.; Wrobel, J.; Yan, G.; Bischoff, E.; Daige, C.; Mohan, R. Discovery of XL335 (WAY-362450): A highly potent, selective, and orally active agonist of the Farnesoid X Receptor (FXR). J. Med. Chem. 2009, 52, 904-907.
21. Mehlmann, J. F.; Crawley, M. L.; Lundquist, J. T., IV; Unwalla,R. J.; Harnish, D. C.; Evans, M. J.; Kim, C. Y.; Wrobel, J. E.; Mahaney, P. E. Pyrrole[2,3-d]azepino compounds as agonists of the farnesoid X receptor (FXR). Bioorg. Med. Chem. Lett. 2009, 19, 5289-5292.
22. Di, L.; Kerns, E.; Li, S.; Petusky, S. High throughput metabolic stability assay for insoluble compounds. Int. J. Pharm. 2006, 317, 54-60.
23. Bohl, C.; Miller, D. D.; Chen, J.; Bell, C.; Dalton, J. Structural basis for accomodation of nonsteroidal ligans in the androgen receptor. J. Biol. Chem. 2005, 280, 37747-37754.
24. Faernegardh, M.; Bonn, T.; Sun, S.; Ljunggren, J.; Ahola, H.; Wilhelmsson, A.; Gustafsson, J.-A.; Carlquist, M. The threedimensional structure of the liver X receptor β reveals a flexible ligand-binding pocket that can accommodate fundamentally different ligands. J. Biol. Chem. 2003, 278, 38821-38828.
25. Langhi, C.; Le May, C.; Kourimate, S.; Caron, S.; Staels, B.; Krempf, M.; Costet, P.; Cariou, B. Activation of the farnesoid X receptor represses PCSK9 expression in human hepatocytes. FEBS Lett. 2008, 582, 949-955.
26. Sanyal, S.; Bavner, A.; Haroniti, A.; Nilsson, L.-M.; Lundasen, T.; Rehnmark, S.; Witt, M. R.; Einarsson, C.; Talianidis, I.; Gustafsson, J.-A.; Treuter, E. Involvement of corepressor complex subunit GPS2 in transcriptional pathways governing human bile acid biosynthesis. Proc. Natl. Acad. Sci. U. S. A. 2007, 104, 15665-15670.
27. Quinet, E. M.; Savio, D. A.; Halpern, A. R.; Chen, L.; Schuster, G. U.; Gustafsson, J. A.; Basso, M. D.; Nambi, P. LiverXreceptor LXR-beta regulation in LXR-alpha-deficient mice: implications for therapeutic targeting. Mol. Pharmacol. 2006, 70, 1340-1349.