Optimization of brain penetrant 11β-hydroxysteroid dehydrogenase type i inhibitors and in vivo testing in diet-induced obese mice

Journal of Medicinal Chemistry

Volumn 57, Issue 3, 2014, Pages 970-986

  Goldberg, Frederick W ^a   Dossetter, Alexander G ^a   Scott, James S ^a   Robb, Graeme R ^a   Boyd, Scott ^a   Groombridge, Sam D ^a   Kemmitt, Paul D ^a   Sjögren, Tove ^a   Gutierrez, Pablo Morentin ^a   Deschoolmeester, Joanne ^a   Swales, John G ^a   Turnbull, Andrew V ^a   Wild, Martin J ^a  

^a ASTRAZENECA   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

11-BETA-HYDROXYSTEROID DEHYDROGENASE TYPE 1; ADAMANTANE; ANIMALS; BLOOD GLUCOSE; BODY WEIGHT; BRAIN; CRYSTALLOGRAPHY, X-RAY; CYCLOPROPANES; DIABETES MELLITUS, TYPE 2; DIETARY FATS; HUMANS; HYPOGLYCEMIC AGENTS; INSULIN; ISOENZYMES; LIVER; MALE; METABOLIC SYNDROME X; MICE; MICE, INBRED C57BL; MICE, OBESE; MODELS, MOLECULAR; PYRAZOLES; RATS; STEREOISOMERISM; STRUCTURE-ACTIVITY RELATIONSHIP; THIAZOLES;

EID: 84894077128     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm4016729     Document Type: Article

References (42)

1. Edwards, C. R. W.; Benediktsson, R.; Lindsay, R. S.; Seckl, J. R. 11β-Hydroxysteroid dehydrogenases: key enzymes in determining tissue-specific glucocorticoid effects Steroids 1996, 61, 263-269
2. Walker, E. A.; Stewart, P. M. 11β-Hydroxysteroid dehydrogenase: unexpected connections Trends Endocrinol. Metab. 2003, 14, 334-339
3. Strain, G. W.; Zumoff, B.; Strain, J. J.; Levin, J.; Fukushima, D. K. Cortisol production in obesity Metab., Clin. Exp. 1980, 29, 980-985
4. Thieringer, R.; Hermanowski-Vosatka, A. Inhibition of 11β-HSD1 as a novel treatment for the metabolic syndrome: do glucocorticoids play a role? Expert Rev. Cardiovasc. Ther. 2005, 3, 911-924
5. Walker, B. R. Glucocorticoids and cardiovascular disease Eur. J. Endocrinol. 2007, 157, 545-559
6. Tomlinson, J. W.; Walker, E. A.; Bujalska, I. J.; Draper, N.; Lavery, G. G.; Cooper, M. S.; Hewison, M.; Stewart, P. M. 11β-Hydroxysteroid dehydrogenase type 1: a tissue-specific regulator of glucocorticoid response Endocr. Rev. 2004, 25, 831-866
7. Yau, J. L.; Noble, J.; Kenyon, C. J.; Hibberd, C.; Kotelevtsev, Y.; Mullins, J. J.; Seckl, J. R. Lack of tissue glucocorticoid reactivation in 11β-hydroxysteroid dehydrogenase type 1 knockout mice ameliorates age-related learning impairments Proc. Natl. Acad. Sci. U.S.A. 2001, 98, 4716-4721
8. Holmes, M. C.; Carter, R. N.; Noble, J.; Chitnis, S.; Dutia, A.; Paterson, J. M.; Mullins, J. J.; Seckl, J. R.; Yau, J. L. 11β- Hydroxysteroid dehydrogenase type 1 expression is increased in the aged mouse hippocampus and parietal cortex and causes memory impairments J. Neurosci. 2010, 30, 6916-6920
9. Sandeep, T. C.; Yau, J. L.; MacLullich, A. M.; Noble, J.; Deary, I. J.; Walker, B. R.; Seckl, J. R. 11β-Hydroxysteroid dehydrogenase inhibition improves cognitive function in healthy elderly men and type 2 diabetics Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 6734-6739
10. Scott, J. S.; Goldberg, F. W.; Turnbull, A. V. Medicinal chemistry of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). J. Med. Chem. [Online early access]. DOI: 10.1021/jm4014746. Published online: December 2, 2013.
11. Anagnostis, P.; Katsiki, N.; Adamidou, F.; Athyros, V. G.; Karagiannis, A.; Kita, M.; Mikhailidis, D. P. 11β-Hydroxysteroid dehydrogenase type 1 inhibitors: novel agents for the treatement of metabolic syndrome and obesity-related disorders? Metabolism 2013, 52, 21-33
12. Rosenstock, J.; Banarer, S.; Fonseca, V. A.; Inzucchi, S. E.; Sun, W.; Yao, W.; Hollis, G.; Flores, R.; Levy, R.; Williams, W. V.; Seckl, J. R.; Huber, R. The 11-β-hydroxysteroid dehydrogenase type 1 inhibitor INCB13739 improves hyperglycemia in patients with type 2 diabetes inadequately controlled by metformin monotherapy Diabetes Care 2010, 33, 1516-1522
13. Bauman, D. R.; Whitehead, A.; Contino, L. C.; Cui, J.; Garcia-Calvo, M.; Gu, X.; Kevin, N.; Ma, X.; Pai, L.-Y.; Shah, K.; Shen, X.; Stribling, S.; Zokian, H. J.; Metzger, J.; Shevell, D. E.; Waddell, S. T.. Evaluation of selective inhibitors of 11β-HSD1 for the treatment of hypertension Bioorg. Med. Chem. Lett. 2013, 23, 3650-3653
14. Shah, S.; Hermanowski-Vosatka, A.; Gibson, K.; Ruck, R. A.; Jia, G.; Zhang, J.; Hwang, P. M. T.; Ryan, N. W.; Langdon, R. B.; Feig, P. U. Efficacy and safety of the selective 11β-HSD1 inhibitors MK-0736 and MK-0916 in overweight and obese patients with hypertension J. Am. Soc. Hypertens. 2011, 5, 166-176
15. Goldberg, F. W.; Leach, A. G.; Scott, J. S.; Snelson, W. L.; Groombridge, S. D.; Donald, C. S.; Bennett, S. N. L.; Bodin, C.; Gutierrez, P. M.; Gyte, A. C. Free-Wilson and structural approaches to co-optimizing human and rodent isoform potency for 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitors J. Med. Chem. 2012, 55, 10652-10661
16. Bisschop, P. H.; Dekker, M. J.; Osterthun, W.; Kwakkel, J.; Anink, J. J.; Boelen, A.; Unmehopa, U. A.; Koper, J. W.; Lamberts, S. W.; Stewart, P. M.; Swaab, D. F.; Fliers, E. Expression of 11β-hydroxysteroid dehydrogenase type 1 in the human hypothalamus J. Neuroendocrinol. 2013, 25, 425-32
17. Savontaus, E.; Conwell, I. M.; Wardlaw, S. L. Effects of adrenalectomy on AGRP, POMC, NPY and CART gene expression in the basal hypothalamus of fed and fasted rats Brain Res. 2002, 958, 130-138
18. Beaulieu, S.; Gagné, B.; Barden, N. Glucocorticoid regulation of proopiomelanocortin messenger ribonucleic acid content of rat hypothalamus Mol. Endocrinol. 1988, 2, 727-731
19. Scott, J. S.; Bowker, S. S.; deSchoolmeester, J.; Gerhardt, S.; Hargreaves, D.; Kilgour, E.; Lloyd, A.; Mayers, R. M.; McCoull, W.; Newcombe, N. J.; Ogg, D.; Packer, M. J.; Rees, A.; Revill, J.; Schofield, P.; Selmi, N.; Swales, J. G.; Whittamore, P. R. O. Discovery of a potent, selective, and orally bioavailable acidic 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitor: Discovery of 2-[(3S)-1-[5-(cyclohexylcarbamoyl)-6- propylsulfanylpyridin-2-yl]-3-piperidyl]acetic acid (AZD4017) J. Med. Chem. 2012, 55, 5951-5964
20. Scott, J. S.; deSchoolmeester, J.; Kilgour, E.; Mayers, R. M.; Packer, M. P.; Hargreaves, D.; Gerhardy, S.; Ogg, D. J.; Rees, A.; Selmi, N.; Stocker, A.; Swales, J. G.; Whittamore, P. R. O. Novel acidic 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitor with reduced acyl glucuronide liability: The discovery of 4-[4-(2-adamantylcarbamoyl)-5- tert -butyl-pyrazol-1-yl]benzoic acid (AZD8329) J. Med. Chem. 2012, 55, 10136-10147
21. Scott, J. S.; Gill, A. L.; Godfrey, L.; Groombridge, S. D.; Rees, A.; Revill, J.; Schofield, P.; Sörme, P.; Stocker, A.; Swales, J. G.; Whittamore, P. R. O. Optimisation of pharmacokinetic properties in a neutral series of 11β-HSD1 inhibitors Bioorg. Med. Chem. Lett. 2012, 22, 6756-6761
22. Di, L.; Rong, H.; Feng, B. Demystifying brain penetration in central nervous system drug discovery J. Med. Chem. 2013, 56, 2-12
23. Desai, P. V.; Raub, T. J.; Blanco, M.-J. How hydrogen bonds impact P-glycoprotein transport and permeability Bioorg. Med. Chem. Lett. 2012, 22, 6540-6548
24. Heffron, T. P.; Salphati, L.; Alicke, B.; Cheong, J.; Dotson, J.; Edgar, K.; Goldsmith, R.; Gould, S. E.; Lee, L. B.; Lesnick, J. D.; Lewis, C.; Ndubaku, C.; Nonomiya, J.; Olivero, A. G.; Pang, J.; Plise, E. G.; Sideris, S.; Trapp, S.; Wallin, J.; Wang, L.; Zhang, X. The design and identification of brain penetrant inhibitors of phosphoinositide 3-kinase α J. Med. Chem. 2012, 55, 8007-8020
25. Bissantz, C.; Kuhn, B.; Stahl, M. A medicinal chemist's guide to molecular interactions J. Med. Chem. 2010, 53, 5061-5084
26. Kotelevtsev, Y.; Brown, R. W.; Fleming, S.; Kenyon, C.; Edwards, C. R. W.; Seckl, J. R.; Mullins, J. J. Hypertension in mice lacking 11β-hydroxysteroid dehydrogenase type 2 J. Clin. Invest. 1999, 103, 683-689
27. Wan, Z.; Chenail, E.; Xiang, J.; Li, H.; Ipek, M.; Bard, J.; Svenson, K.; Mansour, T. S.; Xu, X.; Tian, X.; Suri, V.; Hahm, S.; Xin, Y.; Johnson, C. E.; Li, X.; Qadri, A.; Panza, D.; Perreault, M.; Tobin, J. F.; Saiah, E. Efficacious 11β-hydroxysteroid dehydrogenase type I inhibitors in the diet-induced obesity mouse model J. Med. Chem. 2009, 52, 5449-5461
28. Harno, E.; Cottrell, E. C.; Yu, A.; deSchoolmeester, J.; Gutierrez, P. M.; Denn, M.; Swales, J. G.; Goldberg, F. W.; Bohlooly-Y, M.; Andersén, H.; Wild, M. J.; Turnbull, A. V.; Leighton, B.; White, A. 11β-HSD1 inhibitors still improve metabolic phenotype in male 11β-HSD1 knock-out mice suggesting off-target mechanisms Endocrinology 2013, 154 (10) 4580-4593
29. Fotsch, C.; Bartberger, M. D.; Bercot, E. A.; Chen, M.; Cupples, R.; Emery, M.; Fretland, J.; Guram, A.; Hale, C.; Han, N.; Hickman, D.; Hungate, R. W.; Hayashi, M.; Komorowski, R.; Liu, Q.; Matsumoto, G.; St. Jean, D. J., Jr.; Ursu, S.; Veniant, M.; Xu, G.; Ye, Q.; Yuan, C.; Zhang, J.; Zhang, X.; Tu, H.; Wang, M. Further studies with the 2-amino-1,3-thiazol-4(5H)-one class of 11beta-hydroxysteroid dehydrogenase type 1 inhibitors: reducing pregnane X receptor activity and exploring activity in a monkey pharmacodynamic model J. Med. Chem. 2008, 51, 7953-7967
30. Zhu, Y.; Olson, S. H.; Hermanowski-Vosatka, A.; Mundt, S.; Shah, K.; Springer, M.; Thieringer, R.; Wright, S.; Xiao, J.; Zokian, H.; Balkovec, J. M. 4-Methyl-5-phenyl triazoles as selective inhibitors of 11β-hydroxysteroid dehydrogenase type I Bioorg. Med. Chem. Lett. 2008, 18, 3405-3411
31. Gao, Y. D.; Olson, S. H.; Balkovec, J. M.; Zhu, Y.; Royo, I.; Yabut, J.; Evers, R.; Tan, E. Y.; Tang, W.; Hartley, D. P.; Mosley, R. T. Attenuating pregnane X receptor (PXR) activation: A molecular modelling approach Xenobiotica 2007, 37, 124-138
32. Marino, J. P., Jr.; Mcatee, J. J.; Washburn, D. G. Preparation of nitrogen heterocyclic compounds, particularly substituted piperidines and pyrrolidines, as soluble epoxide hydrolase (sEH) and 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitors and their use. World Patent WO2009070497, 2009.
33. Iyer, A.; Kauter, K.; Alam, M. A.; Hwang, S. H.; Morisseau, C.; Hammock, B. D.; Brown, L. Pharmacological inhibition of soluble epoxide hydrolase ameliorates diet-induced metabolic syndrome in rats Exp. Diabetes Res. 2012, 758614
34. Luria, A.; Bettaieb, A.; Xi, Y.; Shieh, G. J.; Liu, H. C.; Inoue, H.; Tsai, H. J.; Imig, J. D.; Haj, F. G.; Hammock, B. D. Soluble epoxide hydrolase deficiency alters pancreatic islet size and improves glucose homeostasis in a model of insulin resistance Proc. Natl. Acad. Sci. U.S.A. 2011, 108, 9038-9043
35. Leslie, A. G. Integration of macromolecular diffraction data Acta Crystallogr. 2006, D62, 48-57
36. Collaborative Computational Project 4. The CCP4 suite: Programs for protein crystallography Acta Crystallogr. 1994, D50, 750-763
37. Emsley, P.; Cowtan, K. Coot: model-building tools for molecular graphics Acta Crystallogr. 2004, D60, 2126-2132
38. Murshudov, G. N.; Vagin, A. A.; Lebedev, A.; Wilson, K. S.; Dodson, E. J. Efficient anisotropic refinement of macromolecular structures using FFT Acta Crystallogr. 1999, D55, 247-255
39. Blanc, E.; Roversi, P.; Vonrhein, C.; Flensburg, C.; Lea, S. M.; Bricogne, G. Refinement of severely incomplete structures with maximum likelihood in BUSTER-TNT Acta Crystallogr. 2004, D60, 2210-2221
40. Wan, H.; Rehngren, M. High-throughput screening of protein binding by equilibrium dialysis combined with liquid chromatography and mass spectrometry J. Chromatogr. A 2006, 1102, 125-134
41. Wan, H.; Rehngren, M.; Giordanetto, F.; Bergstrom, F.; Tunek, A. High-throughput screening of drug-brain tissue binding and in silico prediction for assessment of central nervous system drug delivery J. Med. Chem. 2007, 50, 4606-4615
42. Rönquist-Nii, Y.; Edlund, P. O. Determination of corticosteroids in tissue samples by liquid chromatography-tandem mass spectrometry J. Pharm. Biomed. Anal. 2005, 37, 341-350