Thyroid receptor ligands. Part 5: Novel bicyclic agonist ligands selective for the thyroid hormone receptor β

Bioorganic and Medicinal Chemistry Letters

Volumn 16, Issue 5, 2006, Pages 1240-1244

  Garcia Collazo, Ana Maria ^a   Koehler, Konrad F ^a   Garg, Neeraj ^a   Färnegårdh, Mathias ^a   Husman, Bolette ^a   Ye, Liu ^a   Ljunggren, Jan ^a   Mellström, Karin ^a   Sandberg, Johnny ^a   Grynfarb, Marlena ^a   Ahola, Harri ^a   Malm, Johan ^a  

^a Karo Bio   (Sweden)

Author keywords

Indane; Indole; Quinoline; Thyroid hormone receptor agonist; TR selectivity; X ray

Indexed keywords

3,5,3' TRIIODO LEVO THYRONINE; HORMONE RECEPTOR STIMULATING AGENT; INDOLE DERIVATIVE; LIGAND; LIOTHYRONINE; THYROID HORMONE RECEPTOR ALPHA; THYROID HORMONE RECEPTOR BETA; THYROMIMETIC AGENT; THYRONINE DERIVATIVE; THYROXINE; UNCLASSIFIED DRUG;

ANIMAL CELL; ARTICLE; BINDING AFFINITY; CHEMICAL STRUCTURE; CRYSTAL STRUCTURE; IC 50; IN VITRO STUDY; LIGAND BINDING; NONHUMAN; RAT; RECEPTOR BINDING; THYROID GLAND; X RAY CRYSTALLOGRAPHY;

ANIMALS; CRYSTALLOGRAPHY, X-RAY; CYCLIZATION; HUMANS; INDOLES; INHIBITORY CONCENTRATION 50; LIGANDS; MOLECULAR STRUCTURE; RATS; SUBSTRATE SPECIFICITY; THYROID HORMONE RECEPTORS BETA; THYROXINE;

ANIMALIA;

EID: 31344475811     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2005.11.077     Document Type: Article

References (21)

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2. The literature suggests many or most effects of thyroid hormones on the heart, and in particular on the heart rate and rhythm, are mediated through the TRα isoform, while most actions of the hormones on the liver and other tissues are mediated more through the β-forms of the receptor: L. Wikström, C. Johansson, C. Salto, C. Barlow, A. Campos Barros, F. Baas, D. Forrest, P. Thoren, and B. Vennström EMBO J. 17 1988 455
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14. These compounds were prepared as in PCT WO2004018421.
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17. 1LBD + 6b were collected at beam line X13, DESY, Hamburg, using a MARCCD detector. Data were collected at 100 K using a wavelength of 0.8013 Å. Data processing was carried out with the HKL suite (Z. Otwinowski, and W. Minor Processing X-ray Diffraction Data Collected in Oscillation Mode Methods in Enzymology 1997 Academic Press New York 307 )
18. 1 structures were TR complexes previously solved. In both cases, refinement was initiated with a round of rigid body refinement followed by simulated annealing starting at 2000 K. Well-defined electron density was observed in the ligand binding clefts in which 6b was built. Refinement and map calculations were performed with CNX (A.T. Brünger, P.D. Adams, G.M. Clore, W.L. DeLano, P. Gros, R.W. Grosse-Kunstleve, J.S. Jiang, J. Kuszewski, M. Nilges, N.S. Pannu, R.J. Read, L.M. Rice, T. Simonson, and G.L. Warren Acta Crystallogr., Sect. D 54 1998 905 )
19. All model building was done with the program 'O' (T.A. Jones, J.Y. Zou, S.W. Cowan, and M. Kjeldgaard Acta Crystallogr., Sect. A 47 1991 110 ). The figure of the ligand binding pocket was produced with Molscript (
20. P. Kraulis J. Appl. Crystallogr. 24 1991 946 ) and rendered with Raster3D (
21. E. Merrit, and M. Murphy Acta Crystallogr., Sect. D 50 1994 869 )