2974 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 16
Communications to the Editor
(14) Zavacki, A. M.; Lehmann, J . M.; Seol, W.; Willson, T. M.; Kliewer,
S. A.; Moore, D. D. Activation of the orphan receptor RIP14 by
retinoids. Proc. Natl. Acad. Sci. U.S.A. 1997, 94, 7909-7914.
(15) Boehm, M. F.; McClurg, M. R.; Pathirana, C.; Mangelsdorf, D.;
White, S. K.; Hebert, J .; Winn, D.; Goldman, M. E.; Heyman, R.
A. Synthesis of high specific activity tritium-labeled [3H]-9-cis-
retinoic acid and its application for identifying retinoids with
unusual binding properties. J . Med. Chem. 1994, 37, 408-414.
(16) Kliewer, S. A.; Lehmann, J . M.; Willson, T. M. Orphan nuclear
receptors: shifting endocrinology into reverse. Science 1999, 284,
757-760.
Refer en ces
(1) Hofmann, A. F. The continuing importance of bile acids in liver
and intestinal disease. Arch. Intern. Med. 1999, 159, 2647-2658.
(2) Angelin, B.; Eriksson, M.; Rudling, M. Bile acids and lipoprotein
metabolism: a renaissance for bile acids in the post-statin era?
Curr. Opin. Lipidol. 1999, 10, 269-274.
(3) Bove, K. E.; Daugherty, C. C.; Tyson, W.; Mierau, G.; Heubi, J .
E.; Balistreri, W. F.; Setchell, K. D. R. Bile acid synthetic defects
and liver disease. Pediatr. Dev. Pathol. 2000, 3, 1-16.
(4) Setchell, K. D. R.; Schwarz, M.; O’Connell, N. C.; Lund, E. G.;
Davis, D. L.; Lathe, R.; Thompson, H. R.; Tyson, R. W.; Sokol,
R. J .; Russell, D. W. Identification of a new inborn error in bile
acid synthesis: mutation of the oxysterol 7R-hydroxylase gene
causes severe neonatal liver disease. J . Clin. Invest. 1998, 102,
1690-1703.
(5) Schwarz, M.; Lund, E. G.; Russell, D. W. Two 7R-hydroxylase
enzymes in bile acid biosynthesis. Curr. Opin. Lipidol. 1998, 9,
113-118.
(6) Kanda, T.; Foucand, L.; Nakamura, Y.; Niot, I.; Besnard, P.;
Fujita, M.; Sakai, Y.; Hatakeyama, K.; Ono, T.; Fujii, H.
Regulation of expression of human intestinal bile acid-binding
protein in Caco-2 cells. Biochem. J . 1998, 330, 261-265.
(7) A unified nomenclature system for the nuclear receptor super-
family. Cell 1999, 97, 161-163.
(8) 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.
(9) Makishima, M.; Okamoto, A. Y.; Repa, J . J .; Tu, H.; Learned,
R. M.; Luk, A.; Hull, M. V.; Lustig, K. D.; Mangelsdorf, D. J .;
Shanz, B. Identification of a nuclear receptor for bile acids.
Science 1999, 284, 1362-1365.
(10) Wang, H.; Chen, J .; Hollister, K.; Sowers, L. C.; Forman, B. M.
Endogenous bile acids are ligands for the nuclear receptor FXR/
BAR. Mol. Cell 1999, 3, 543-553.
(11) Grober, J .; Zaghini, I.; Fujii, H.; J ones, S. A.; Kliewer, S. A.;
Willson, T. M.; Ono, T.; Besnard, P. Identification of a bile acid-
responsive element in the human ileal bile acid-binding protein
gene. Involvement of the farnesoid X receptor/9-cis-retinoic acid
receptor heterodimer. J . Biol. Chem. 1999, 274, 29749-29754.
(12) Chiang, J . Y. L.; Kimmel, R.; Weinberger, C.; Stroup, D.
Farnesoid X receptor responds to bile acids and represses
cholesterol 7R-hydroxylase gene (CYP7A1) transcription. J . Biol.
Chem. 2000, 275, 10918-10924.
(13) Setchell, K. D. R.; Rodrigues, C. M. P.; Clerici, C.; Solinas, A.;
Morelli, A.; Gartung, C.; Boyer, J . Bile acid concentrations in
human and rat liver tissue and in hepatocyte nuclei. Gastroen-
terology 1997, 112, 226-235.
(17) Haffner, C. D.; Fivush, A. M.; Maloney, P. R. Unpublished
results. The design and synthesis of this library will be described
separately.
(18) The LiSA measures the ability of FXR ligands to induce
association of the coactivator protein SRC1 with the receptor,
which is the first step in the signal transduction process that
leads to regulation of gene transcription. The partial recruitment
of SRC1 to FXR by 1 may be responsible for its low agonist
potency in cell-based reporter assays. See: Xu, L.; Glass, C. K.;
Rosenfeld, M. G. Coactivator and corepressor complexes in
nuclear receptor function. Curr. Opin. Genet. Dev. 1999, 9, 140-
147.
(19) Katritzky, A. R.; Toader, D.; Watson, K.; Kiely, J . S. New
synthesis of Sasrin resin. Tetrahedron Lett. 1997, 38, 7849-
7850.
(20) Doyle, F. P.; Haison, J . C.; Long, A. W.; Nagler, J . H. C.; Stove,
E. R. Derivatives of 6-aminopenicillanic acid. Part VI. Penicillins
from 3- and 5-phenylisoxazole-4-carboxylic Acids and their alkyl
and halogen derivatives. J . Chem. Soc. 1963, 5838-5845.
(21) Singh, B.; Lesher, G. Y. Convenient preparations of ethyl
3-oxopentanoate and 3,5-disubstituted 1,2-oxazole-4-carboxylic
acids from a common type of intermediate. Synthesis 1978, 829-
830.
(22) Goodwin, B.; J ones, S. A.; Price, R. R.; Watson, M. A.; McKee,
D. D.; Moore, L. B.; Galardi, C.; Wilson, J . G.; Lewis, M. C.; Roth,
M. E.; Maloney, P. R.; Willson, T. M.; Kliewer, S. A. A Regulatory
cascade of the nuclear receptors FXR, SHP-1 and LRH-1
represses bile acid biosynthesis. Submitted for publication.
(23) Isler, J . H.; Sali, A. Chenodeoxycholic acid: a review of its
pharmacological properties and therapeutic use. Drugs 1981, 21,
90-119.
J M0002127