Discovery of a tetrazole-based growth hormone secretagogue: 4-(Hydroxybutyl)carbamic acid 2-{5-[1-(2-amino-2-methylpropionylamino)-2- benzyloxyethyl]tetrazol-1-yl}ethyl ester (BMS-317180)

Journal of Medicinal Chemistry

Volumn 50, Issue 24, 2007, Pages 5890-5893

  Li, Jun ^a   Chen, Stephanie Y ^a   Li, James J ^a   Wang, Haixia ^a   Hernandez, Andres S ^a   Tao, Shiwei ^a   Musial, Christa M ^a   Qu, Fucheng ^a   Swartz, Stephen ^a   Chao, Sam T ^a   Flynn, Neil ^a   Murphy, Brian J ^a   Slusarchyk, Dorothy A ^a   Seethala, Ramakrishna ^a   Yan, Mujing ^a   Sleph, Paul ^a   Grover, Gary ^a   Smith, Mark A ^a   Beehler, Blake ^a   Giupponi, Leah ^a   Dickinson, Kenneth E ^a   Zhang, Hongjian ^a   Humphreys, William G ^a   Patel, Bharat P ^a   Schwinden, Mark ^a   Stouch, Terry ^a   Cheng, Peter T W ^a   Biller, Scott A ^a   Ewing, William R ^a   Gordon, David ^a   Robl, Jeffrey A ^a   Tino, Joseph A ^a   more..

^a BRISTOL MYERS SQUIBB   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

4 (HYDROXYBUTYL)CARBAMIC ACID 2 [5 [1 (2 AMINO 2 METHYLPROPIONYLAMINO) 2 BENZYLOXYETHY]TETRAZOL 1 YL]ETHYL ESTER; BMS 317180; GROWTH HORMONE SECRETAGOGUE; TETRAZOLE DERIVATIVE; UNCLASSIFIED DRUG;

ARTICLE; CONTROLLED STUDY; DOG; DRUG BIOAVAILABILITY; DRUG CLEARANCE; DRUG EFFICACY; DRUG HALF LIFE; DRUG POTENCY; DRUG SAFETY; MONKEY; NONHUMAN;

ADMINISTRATION, ORAL; ANIMALS; BIOLOGICAL AVAILABILITY; CARBAMATES; DOGS; ESTERS; GROWTH HORMONE; HUMAN GROWTH HORMONE; HUMANS; MACACA FASCICULARIS; RATS; SOLUBILITY; STRUCTURE-ACTIVITY RELATIONSHIP; TETRAZOLES; WATER;

EID: 37849000897     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm7010595     Document Type: Article

References (39)

1. (a) Strobl, J. S.; Thomas, M. J. Human growth hormone. Pharmacol. Rev. 1993, 46, 1-34.
2. (b) Rosen, T.; Johannsson, G.; Johansson, J.-O.; Bengtsson, B.-A. Consequences of growth hormone deficiency in adults and the benefits and risks of recombinant human growth hormone treatment. Horm. Res. 1995, 43, 93-99.
3. Momany, F. A.; Bowers, C. Y.; Reynolds, G. A.; Chang, D.; Hong, A.; Newlander, K. Design, synthesis, and biological activity of peptides which release growth hormone in vitro. Endocrinology 1981, 108, 31-39.
4. (a) Sartor, O.; Bowers, C. Y.; Chang, D. Parallel studies of His-D-Trp-Ala-Tip-D-Phe-Lys-NH2 and human pancreatic growth hormone-releasing factor-44-NH2 in rat primary pituitary cell monolayer culture. Endocrinology 1984, 116, 952-957.
5. (b) Bowers, C. Y.; Momany, F. A.; Reynolds, G. A.; Hong, A.; Newlander, K. On the in vitro and in vivo activity of a new synthetic hexapeptide that acts on the pituitary to specifically release growth hormone. Endocrinology 1984, 114, 1537-1545.
6. (a) Akman, A. S.; Girard, M.; O'Brien, L. F.; Ho, A. K.; Chik, C. L. Mechanisms of actions of a 2nd generation growth hormone-releasing peptide (Ala-His-D-beta-Nal-Ala-Trp-D-Phe-Lys-NH2) in rat anterior-pituitary cells. Endocrinology 1993, 132, 1286-1291.
7. (b) For a review on the clinical actions of GHRPs, see: Ghigo, E.; Arvat, E.; Muccioli, G.; Camanni, F. Growth hormone releasing peptides. Eur. J. Endocrinol. 1997, 136, 445-460, and references therein.
8. (a) Smith, R. G.; Cheng, K.; Pong, S. S.; Hickey, H.; Jacks, T.; Butler, B.; Chan, W.-S.; Chaung, L. Y. P.; Judith, F.; Taylor, J. A.; Wyvratt, M. J.; Fisher, M. H. A novel non-peptidyl growth hormone secretagogue. Science 1993, 260, 1640-1643.
9. (b) Pong, S.-S.; Chaung, L.-Y. P.; Dean, D. C.; Nargund, R. P.; Patchett, A. A.; Smith, R. G. Identification of a new G-protein-linked receptor for growth hormone secretagogues. Mol. Endocrinol. 1996, 10, 57-61.
10. (a) Schoen, W. R.; Pisano, J. M.; Prendergast, K.; Wyvratt, M. J., Jr.; Fisher, M. H.; Cheng, K.; Chan, W. W. S.; Butler, B.; Smith, R. G.; Ball, R. G. A novel 3-substituted benzazepinone growth hormone secretagogue (L-692,429). J. Med. Chem. 1994, 37, 897-906.
11. (b) Patchett, A. A.; Nargund, R. P.; Tata, J. R.; Chen, M.-H.; Barkat, K. J.; Johnston, D. B. R.; Cheng, K.; Chan, W. W.-S.; Butler, B.; Hickey, G.; Jacks, T.; Schleim, K.; Pong, S.-S.; Chaung, L.-Y. P.; Chen, H. Y.; Frazier, E.; Leung, K. H.; Chiu, S.-H. L.; Smith, R. G. Design and biological activities of L-163,191 (MK-0677): A potent orally active growth hormone secretagogue. Proc. Natl. Acad. Sci. U.S.A. 1995, 92, 7001-7005.
12. (a) Yang, L.; Morriello, G.; Patchett, A. A.; Leung, K.; Jacks, T.; Cheng, K.; Schleim, K. D. Feeney, W.; Chan, W. W.-S.; Chiu, S. L.; and Smith, R. G. 1-[2(R)-(2-Amino-2-methylpropionylamino)-3-(1H-indol-3-yl)propionyl]- 3-benzylpiperidine-3(S)-carboxylic Acid Ethyl Ester (L-163,540): A potent, orally bioavailable, and short-duration growth hormone secretagogue. J. Med. Chem. 1998, 41, 2439-2441.
13. (b) Hansen, T. K.; Ankersen, M.; Hansen, B. S.; Raun, K.; Nielsen, K. K.; Lau, J.; Peschke, B.; Lundt, B. F.; Thgersen, H.; Johansen, N. L.; Madsen, K.; Andersen, P. H. Novel orally active growth hormone secretagogues. J. Med. Chem. 1998, 41, 3705-3714.
14. (c) Carpino, P. A.; Lefker, B. A.; Toler, S. M.; Pan, L. C.; Hadcock, J. R.; Murray, M. C.; Cook, E. R.; DiBrino, J. N.; DeNinno, S. L;. Chidsey-Frink, K. L;. Hada, W. A.; Inthavongsay, J.; Lewis, S. K.; Mangano, F. M.; Mullins, M. A.; Nickerson, D. F., Ng, O.; Pirie, C. M.; Ragan, J. A.; Rose, C. R.; Tess, D. A.; Wright, A. S.; Yu, L.; Zawistoski, M. P.; Pettersen, J. C.; DaSilva-Jardine, P. A.; Wilson, T. C.; Thompson, D. D. Discovery and biological characterization of capromorelin analogues with extended half-lives. Bioorg. Med. Chem. Lett. 2002, 12, 3279-3282.
15. (d) For an excellent review, see: Nargund, R. P.; Patchett, A. A.; Bach, M. A.; Murphy, M. G.; Smith, R. G. Peptidomimetic growth hormone secretagogues. Design considerations and therapeutic potential. J. Med. Chem. 1998, 41, 3103-3127.
16. Kojima, M.; Hosoda, H.; Date, Y.; Nakazato, M.; Matsuo, H.; Kangawa, K. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 1999, 402, 656-660.
17. (a) Cao, J.-M; Ong, H.; Chen C. Effects of ghrelin and synthetic GH secretagogues on the cardiovascular system. Trend in Endocrinology and Metabolism 2006, 17 (1), 13-18.
18. (c) Smith, R. G. Development of Growth Hormone Secretagogues. Endocrine Review 2005, 26 (3), 346-360.
19. (b) Smith, R. G.; Jiang, H.; Sun, Y. Developments in ghrelin biology and potential clinical relevance. Trends Endocrinol. and Metab. 2005, 16, 436-442.
20. (a) Yavuzsen, T.; Davis, M. P.; Walsh, D.; LeGrand, S.; Lagman, R. Systematic review of the treatment of cancer-associated anorexia and weight loss. J. Clin. Oncol. 2005, 23, 8500-8511.
21. (b) Garcia, J. M.; Garcia-Touza, M.; Hijazi, R. A.; Taffet, G.; Epner, D.; Mann, D.; Smith, R. G.; Cunningham, G. R.; Marcelli, M. Active ghrelin levels and active to total ghrelin ratio in cancer-induced cachexia. J. Clin. Endocrinol. Metab. 90, 2920-2926.
22. (c) Ramos, E. J. B.; Suzuki, S.; Marks, D.; Inui, A.; Asakawa, A.; Meguid, M. M. Anorexia-cachexia syndrome: cytokines and neuropeptides. Curr. Opin. Clin. Nutr. Metab. Care 2004, 7, 427-434.
23. (a) Spatola, A. F. Peptide backbone modifications: A structure-activity analysis of peptides containing amide bond surrogates, conformational constraints, and related backbone replacements. Chem. Biochem. Amino Acids, Peptides, Proteins 1983, 7, 267-57.
24. (b) Liskaamp, R. M. J. Conformationally restricted amino acids and dipeptides, (Non)peptidomimetics and secondary structure mimetics. Recl. Trav. Chim. Pays-Bas 1994, 113, 1.
25. (c) Borg, S.; Estenne-Bouhtou, G.; Luthman, K.; Csoregh, I.; Hesselink, W.; Hacksell, U. Synthesis of 1,2,4-oxadiazole-, 1,3,4-oxadiazole-, and 1,2,4-triazole-derived dipeptidomimetics. J. Org. Chem. 1995, 60, 3112.
26. (d) Ahn, J.-M.; Boyle, N. A.; MacDonald, M. T.; Janda, K. D. Peptidomimetics and peptide backbone modifications. Mini-Rev. Med. Chem. 2002, 2, 463-473.
27. (a) Zabrocki, J.; Smith, G. D.; Dunbar, J. B., Jr.; Ijima, H.; Marshall, G. R. Conformational mimicry. 1. 1,5-Disubstituted tetrazole ring as a surrogate for the cis amide bond. J. Am. Chem. Soc. 1988, 110, 5875-5880.
28. (b) Beusen, D. D.; Zabrocki, J.; Slomczynska, U.; Head, R. D.; Kao, J. L.; Marshall, G. R Conformational mimicry: Synthesis and solution conformation of a cyclic somatostatin hexapeptide containing a tetrazole cis amide bond surrogate. Biopolymers 1995, 36, 181-200.
29. (c) Zabrocki, J.; Marshall, G. R. The 1,5-disubstituted tetrazole ring as a cis-amide bond surrogate. Methods Mol. Med. 1999, 23, 417-436.
30. (d) Boteju, L. W.; Hruby, V. J. Tryptophan-containing 1,5-tetrazole dipeptide analogs: Synthesis of TrpΨ[CN4]Nle as a cis amide bond surrogate. Tetrahedron Lett. 1993, 34, 1757-1760.
31. (e) Duncia, J. V.; Santella, J. B., III; Higley, C. A.; VanAtten, M. K.; Weber, P. C.; Alexander, R. S.; Kettner, C. A.; Pruitt, J. R.; Liauw, A. Y.; Quan, M. L.; Knabb, R. M.; Wexler, R. R. Pyrazoles, 1,2,4-triazoles, and tetrazoles as surrogates for cis-amide bonds in boronate ester thrombin inhibitors. Bioorg. Med. Chem. Lett. 1998, 8, 775-780.
32. (f) Hernandez, A. S.; Cheng, P. T. W.; Musial, C. M.; Swartz, S. G.; George, R. J.; Grover, G.; Slusarchyk, D.; Seethala, R. K.; Smith, M.; Dickinson, K.; Giupponi, L.; Longhi, D. A.; Flynn, N.; Murphy, B. J.; Gordon, D. A.; Biller, S. A.; Robl, J. A.; Tino, J. A., Discovery, synthesis and structure activity studies of tetrazole based growth hormone secretagogues, Bioorg. Med. Chem. Lett. 2007, 17, 5928-5933.
33. Duncia, J. V.; Pierce, M. E.; Santella, J. B. III Three synthetic routes to a sterically hindered tetrazole. A new one-step mild conversion of an amide into a tetrazole. J. Org. Chem. 1991, 56, 2395-2400.
34. (a) Sullivan, E.; Tucker, E. M.; Dale, I. L. Methods Mol. Biol. 1999, 114, 125-133.
35. (b) Schroeder, K. S.; Neagle, B. D. J. Biomol. Screening 1996, 1, 75-80.
36. (a) Cells overexpressing endogenous human growth hormone secretagogue receptor by random activation of gene expression (RAGE) (Athersys, Inc.) technology was used. The EC50 was measured by determining the intracellular calcium concentration in a FLIPR assay with ghrelin as having 100% intrinsic functional activity. All EC50 values are the averages of multiple measurements.
37. (b) Harrington, J. J.; Sherf, B.; Rundlett, S.; Jackson, P. D.; Perry, R.; Cain, S.; Leventhal, C.; Thornton, M.; Ramachandran, R.; Whittington, J.; Lerner, L.; Costanzo, D.; McElligott, K.; Boozer, S.; Mays, R.; Smith, E.; Veloso, N.; Klika, A.; Hess, J.; Cothren, K.; Lo, K.; Offenbacher, J.; Danzig, J.; Ducar, M. Nat. Biotechnol. 2001, 19, 440-445.
38. Fasted male Wistar rats (200-250 g) were anesthetized via intraperitoneal injection with ketamine (30 mg) and xylazine (10 mg) per kilogram of body weight. The drug or vehicle (10% ethanol, 0.09% saline v/v) was administered intravenously at a volume of 10 mL/kg to a group of five rats. After 15 min, a 1.5 mL blood sample was drawn from the abdominal aorta. Plasma samples were then assayed for rat growth hormone by radioimmunoassay using a modification of the kit supplied by the National Pituitary Hormone Center (Dr. A. Parlow, Harbor-UCLA Medical Center, Los Angeles, CA).
39. The PanLabs Spectrum Screen is a proprietary in vitro screen using a panel of 85 receptors and ion channels.