• Overview
• VirtualToxLab
• Ah Receptor
• Estrogen Receptor
• Androgen Receptor
• Thyroid Receptor
• PPAR γ
• Glucocorticoid
• Mineralocorticoid
• CYP 3A4
• CYP 2A13
• Bradykinin B₂
• CCR-3
• NK-1
• Ochratoxin A
• Biological Data

BIOLOGICAL DATA UNDERLYING THE QSAR MODELS

Bandiera, S., Sawyer,T., Romkes, M., Zmudzka, B., Safe, L., Mason, G., Keys, B. and Safe, S. (1984). Polychlorinated dibenzofurans (PCDFs): Effects of structure on binding to the 2,3,7,8-TCDD cytosolic receptor protein, AhR induction and toxicity. Toxicology 32, 131–144.

Bandiera, S., Safe, S. and Okey, A.B. (1982). Binding of polychlorinated biphenyls classified as either phenobarbitone, 3-methylcholanhene or mixed-type inducers to cytosolic Ah receptor. Chem.-Biol. Interactions. 39, 259–277.

Denomme, M.A., Homonko, K., Fujita, T., Sawyer, T. and Safe, S. (1986). Substituted polychlorinated dibenzofuran receptor-binding affinities and hydrocarbon hydroxylase induction potenties — A QSAR analysis. Chem.-Biol. Interactions 57, 175–187.

Denomme, M.A., Homonko, K., Fujita, T., Sawyer, T. and Safe, S. (1985). Effects of substituents on the cytosolic receptor-binding avidities and aryl hydrocarbon hydroxylase induction potencies of 7-substituted 2,3-dichlorodibenzo-p-dioxins. Mol. Pharmacol. 27, 656–661.

Gasiewics, T.A., Kende, A.S., Rucci, G., Whitney, B., Willey, J.J. (1996). Analysis of structural requirements for Ah receptor antagonist activity: ellipticines, flavones, and related compounds. Biochem. Pharmacol. 52, 1787–1803.

Mason, G., Farell, K., Keys, B., Piskorska-Plisczynska, J., Safe, L. and Safe, S. (1986). Polychlorinated dibenzo-p-dioxins: Quantitative in vitro and in vivo structure-activity relationships. Toxicology, 41, 21–31.

Mason, G., Sawyer,T., Keys, B., Bandiera, S., Romkes, M., Piskorska-Plisczynska, J., Zmudzka, B. and Safe, S. (1985). Polychlorinated dibenzofurans (PCDFs): Correlation between in vivo and in vitro structure-activity relationships. Toxicology 37, 1–12.

Romkes, M., Piskorska-Plisczynska, J., Keys, B., Safe, S. and Fujita, T. (1987). Quantitative-Structure-Activity Relationships: Analysis of interactions of 2,3,7,8-tetrachlorodibenzo-p-dioxin and 2-substituted analogues with rat, mouse, guinea pig, and hamster cytosolic receptor. Cancer Research 47, 5108–5111.

Safe, S. (1990). Polychlorinated biphenyls (PCBs), dibenzo-p-dioxins (PCDDs), dibenzofurans (PCDFs) and related compounds: Environmental and mechanistic considerations which support the development of toxic equivalency factors (TEFs). CRC Crit. Rev. Toxicol. 21, 51–88.

Safe, S. and Krishnan, K. (1995). Cellular and molecular biology of Aryl hydrocarbon (Ah) receptor-mediated gene expression. In: Archives of Toxicology, Supplement 17, Degen, D.H., Seiler, J.P. and Bentley, P. (Eds.), Springer, Berlin, pp. 116–124.

Estrogen receptor α/β

Blair, R.M., Fang, H., Branham, W.S., Hass, B.S., Moland, C.L., Tong, W., Shi, L., Perkins, R. Sheehan, D.M. (2000). The estrogen receptor relative binding affinities of 188 natural and xenochemicals: structural diversity of ligands. Toxicol. Sci. 54, 138–153.

Malamas, M.S., Manas, E.S., McDevitt, R.E., Gunawan, I., Xu, Z.B., Collini, M.D., Miller, C.P., Dinh, T., Henderson, R.A., Keith jr., J.C., Harris, H.A. (2004). Design and synthesis of aryl diphenolic azoles as potent and selective estrogen receptor ligands. J. Med. Chem. 47, 5021–5040.

Shi, L.M., Fang, H., Tong, W., Wu, J., Perkins, R., Blair, R.M., Dial, S.L., Moland, C.L., Sheehan, D.M. (2001). QSAR Models using a large diverse set of estrogens. J. Chem. Inf. Comput. Sci. 41, 186–195.

Androgen receptor

Fang, H., Tong, W., Branham, W.S., Moland, C.L., Dial, S.L., Hong, H., Xie, Q., Perkins, R., Owens, W., Sheehan, D.M. Study of 202 natural, synthetic, and environmental chemicals for binding to the androgen receptor. Chem. Res. Toxicol. 2003, 16, 1338–1358.

Thyroid receptor α/β

Dow, R.L., Schneider, S.R., Paight, E.S., Hank, R.F., Chiang, P., Cornelius, P., Lee, E., Newsome, W.P., Swick, A.G., Spitzer, J., Hargrove, D.M., Patterson, T.A., Pandit, J., Chrunyk, B.A., LeMotte, P.K., Danley, D.E., Rosner, M.H., Ammirati, M.J., Simons, S.P., Schulte, G.K., Tate, F., DaSilva-Jardinea, P. (2003). Doscovery of a novel series of 6-azauracil-based thyroid hormone receptor ligands: potent TR beta subtype-selective thyromimetics. Bioorg. Med. Chem. Lett. 13, 379–382.

Hangeland, J.J., Doweyko, A.M., Dejneka, T., Friends, T.J., Devastale, P., Mellstrøm, K., Sandberg, J., Grynfarb, M., Sack, J.S., Einspahr, H., Färnegardh, M., Husman, B., Ljunggren, J., Koehler, K.F., Sheppard, C., Malm, J.J., Ryono, D.E. (2004). Thyroid receptor ligands. 2. Thyromimetics with improved selectivity for thyroid hormone receptor β. Bioorg. Med. Chem. Lett. 14, 3549–3553.

Hedfors, A., Appleqvist, T. Carlsson, B., Bladh, L.G., Litten, C., Agback, P., Grynfarb, M., Koehler, K.F., Malm, J.J. (2005). Thyroid receptor ligands. 3. Design and synthesis of 3,5-dihalo-4-alkoxyphenylalkanoic acids as indirect antagonists of the thyroid hormone receptor. J. Med. Chem. 48, 3114–3117.

Ye, L., Li, Y.L., Mellstrøm, K., Mellin, C., Bladh, L.G., Koehler, K.F., Garg, N., Garcia Collazom, A.M., Litten, C., Husman, B., Persson, K., Ljunggren, J., Grover, G., Sleph, P.G., George, R., Malm, J.J. (2003). Thyroid receptor ligands. 1. Agonist ligands selective for the thyroid receptor: 1. J. Med. Chem. 46, 1580–1588.

Peroxisome proliferator-activated receptor γ

Liao, C., Xie, A., Zhou, J., Shi, L., Li, Z., Lu, X.P., 2004. 3D QSAR studies on peroxisome proliferator-activated receptor γ agonists using CoMFA and CoMSIA. J. Mol. Model. 10, 165–177.

Glucocorticoid receptor

Ali A., Thompson C.F., Balkovec J.M., and 20 others (2004). Novel N-arylpyrazolo-[3,2-c]-based ligands for the glucocorticoid receptor: receptor binding and in vivo activity. J. Med. Chem. 47, 2441–2452.

Coghlan M.J., Kym P.R., Elmore S.W. and 10 others (2001). Synthesis and characterization of non-steroidal ligands for the Glucocorticoid Receptor: selective quinoline derivatives with prednisolone-equivalemt functional activity. J. Med. Chem. 44, 2879–2885.

Einstein M., Greenlee M., Rouen G. and 17 others (2004). Selective glucocorticoid receptor nonsteroidal ligands completely antagonize the dexamethasone mediated induction of enzymes involved in gluconeogenesis and glutamine metabolism. J. Steroid Biochem. Molec. Biol. 92, 345–356.

Elmore S.W., Coghlan M.J., Anderson D.D. and 10 others (2001). Nonsteroidal selective glucocorticoid modulators: the effect of C-5 alkyl substitution on the transcriptional activation/repression profile of 2,5-dihydro-10-methoxy-2,2,4-trimethyl-1H-[1]benzopyrano[3,4-f]quinolines. J. Med. Chem. 44, 4481–4491.

Hammer S., Spika I., Sippl W. and 8 others. (2003). Glucocorticoid receptor interactions with glucocorticoids: evaluation by molecular modeling and functional analysis of glucocorticoid receptor mutants. Steroids 68, 329–339.

Smith C.J., Ali A., Balkovec J.M. and 24 others (2005). Novel ketal ligands for the glucocorticoid receptor: in vitro and in vivo activity. Bioorg. Med. Chem. Lett. 15, 2926–2931

Cytochrome P450 3A4

S. Wanchana, F. Yamashita, M. Hashida (2003). QSAR analysis of the inhibition of recombinant CYP 3A4 activity by structurally diverse compounds using a genetic algorithm-combined partial least-squares method. Pharm. Res. 20, 1401–1408.

NK-1 receptor

Dollinger H., (1998). Chemical Research, Boehringer Ingelheim Pharma & Co. KG (Biberach/Riss, Germany), personal communication.

CCR-3 receptor

DeLucca, G.V., Kim, U.I., Johnson, C., Vargo, B.J., Welch, P.K., Covington, M., Davies, P., Solomon, K., Newton, R.C., Trainor, G.L., Devicco, C.P., So, S.S. (2002). Discovery and structure-activity relationship of N-(Ureidoalkyl)-benzyl-piperidines as potent small molecule CC chemokine receptor-3 (CCR3) antagonists. J. Med. Chem. 45, 3794–3804.

Dollinger H., (2003). Chemical Research, Boehringer Ingelheim Pharma & Co. KG (Biberach/Riss, Germany), personal communication.

Bradykinin B₂ receptor

Abe, Y., Kayakiri, H., Satoh, S., Inoue, T., Sawada, Y., Inamura, N., Asano, M., Aramori, I., Hatori, C., Sawai, H., Oku, T., Tanaka, H. (1998). A novel class of orally active non-peptide bradykinin B2 receptor antagonists. 4. Discovery of novel frameworks mimicking the active conformation. J. Med. Chem. 41, 4587–4598.

Abe, Y., Kayakiri, H., Satoh, S., Inoue, T., Sawada, Y., Inamura, N., Asano, M., Aramori, I., Hatori, C., Sawai, H., Oku, T., Tanaka, H. (1998). A novel class of orally active non-peptide bradykinin B2 receptor antagonists. 3. Discovering bioisosteres of the imidazo[1,2-a]pyridine moiety. J. Med. Chem. 41, 4062–4079.

Abe, Y., Kayakiri, H., Satoh, S., Inoue, T., Sawada, Y., Inamura, N., Asano, M., Hatori, C., Sawai, H., Oku, T., Tanaka, H. (1998)A novel class of orally active non-peptide bradykinin B2 receptor antagonists. 2. Overcoming the species difference between guinea pig and man. J. Med. Chem. 1998, 41, 4053–4061.

Abe, Y., Kayakiri, H., Satoh, S., Inoue, T., Sawada, Y., Imai, K., Inamura, N., Asano, M., Hatori, C., Katayama, A., Oku, T., Tanaka, H. (1998). A novel class of orally active non-peptide bradykinin B2 receptor antagonists. 1. Construction of the basic framework. J. Med. Chem. 41, 564–578.

Sawada, Y., Kayakiri, H., Abe, Y., Mizutani, T., Inamura, N., Asano, M., Hatori, C., Aramori, I., Oku, T., Tanaka, H. (2004). Discovery of the first non-peptide full agonists for the human bradykinin B2 receptor incorporating 4-(2-picolyloxy)-quinoline and 1-(2-picolyl)benzimidazole frameworks. J. Med. Chem. 47, 2853–2863.

Sawada, Y., Kayakiri, H., Abe, Y., Mizutani, T., Inamura, N., Asano, M., Aramori, I., Hatori, C., Oku, T., Tanaka, H. (2004). A new class of nonpeptide bradykinin B2 receptor ligand, incorporating a 4 aminoquinoline framework. Identification of a key pharmacophore to determine species difference and agonist/antagonist profile. J. Med. Chem. 47, 2667–2677.

Sawada, Y., Kayakiri, H., Abe, Y., Imai, K., Mizutani, T., Inamura, N., Asano, M., Aramori, I., Hatori, C., Katayama, A., Oku, T., Tanaka, H. (2004). A new series of highly potent non-peptide bradykinin B2 receptor antagonists incorporating the 4-heteroarylquinoline framework. Improvement of aqueous solubility and new insights into species difference. J. Med. Chem. 47, 1617–1630.