´
A. S. Hernandez et al. / Bioorg. Med. Chem. Lett. 18 (2008) 2067–2072
2072
8. Carpino, P. A. Exp. Opin. Ther. Patents 2002, 12, 1599.
9. Dodge, J. A.; Heiman, M. L. Annu. Rep. Med. Chem.
2003, 38, 81.
Acknowledgments
We thank Dr. William Washburn, Dr. Peter T.W.
Cheng and Dr. Robert Zahler for their suggestions on
the manuscript.
10. Pan, L. C.; Carpino, P. A.; Lefker, B. A.; Ragan, J. A.;
Toler, S. M.; Pettersen, J. C.; Nettleton, D. O.; Ng, O.;
Pirie, C. M.; Chidsey-Frink, K.; Lu, B.; Nickerson, D. F.;
Tess, D. A.; Mullins, M. A.; MacLean, D. B.; Da Silva-
Jardine, P. A.; Thompson, D. D. Endocrine 2001, 14, 437.
11. (a) Seyler, D. E.; Dodge, J. A.; Osborne, J. J.; Cox, K. L.;
Viswanath, D.; Wilmot, A. F.; Keaton, M. J.; Heiman, M.
L.; Bryant, H. U.; Cutler, G. B., Jr. Drug Dev. Res. 2000,
49, 260; (b) Lugar, C. W.; Clay, M. P.; Lindstrom, T. D.;
Woodson, A. L.; Smiley, D.; Heiman, M. L.; Dodge, J. A.
Bioorg. Med. Chem. Lett. 2004, 14, 5873.
References and notes
1. Rivier, J.; Spiess, J.; Thorner, M.; Vale, W. Nature 1982,
300, 276.
2. (a) Bowers, C. Y. In Growth Hormone Secretagogues;
Bercu, B. B., Walker, R. F., Eds.; Springer-Verlag: New
York, 1996; pp 9–28; (b) Bowers, C. Y.; Reynolds, G. A.;
Durham, D.; Barrera, C. M.; Pezzoli, S. S.; Thorner, M.
O. J. Clin. Endocrinol. Metab. 1990, 70, 975.
´
12. 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. Bioorg. Med. Chem. Lett. 2007,
17, 5928.
3. Reichlin, S.; Saperstain, R.; Jackson, I. M. D.; Boyd, A.
E.; Patel, Y. Ann. Rev. Physiol. 1976, 38, 389.
4. Howard, A. D.; Feighner, S. D.; Cully, D. F.; Arena, J. P.;
Liberator, P. A.; Rosenblum, C. I.; Hamelin, M.; Hreniuk,
D. L.; Palyha, O. C.; Anderson, J.; Paress, P. S.; Diaz, C.;
Chou, M.; Liu, K. K.; McKee, K. K.; Pong, S.-S.; Chaung,
L.-Y. P.; Elbrecht, A.; Dashkevicz, M.; Heavens, R.; Rigby,
M.; Sirinathsinghji, D. J. S.; Dean, D. C.; Melillo, D. G.;
Patchett, A. A.; Nargund, R. P.; Griffin, P. R.; DeMartino,
J. A.; Gupta, S. K.; Schaeffer, J. M.; Smith, R. G.; Van der
Ploeg, L. H. T. Science 1996, 273, 974.
13. 1H NMR easily distinguished between the 1H and 2H
isomers by comparison of the Dd between the methyls of
the 2-aminoisobutyric fragment. The Dd is significantly
larger in the 1H isomer than in the 2H isomer.
14. A dose response for MK-677 was performed in order to
benchmark tetrazole analogs versus a well studied refer-
ence. At the highest dose utilized, 5.23 lmol/kg, there was
no evidence of a plateau in the response. Higher doses
could not be achieved as toxicity was observed and
therefore an ED50 could not be determined. Since the
maximal tolerated dose of MK-677 effects a 500% increase
in GH, in vivo potencies for tetrazole based GHS are
expressed as ED250 or the dose at which a 250% increase in
plasma GH is achieved. The ED250 of MK-677 is
0.46 lmol/kg.
15. Analytical HPLC conditions: Column: Zorbax SB C18,
4.6 · 75 mm; Grad. T: 8 min; Flow R.: 2.5 mL/min.;
Solvent Grad.: 0–100% B; Wave: 220 nm (A = 10% MeOH
À90% H2O À0.2% H3PO4; B = 90% MeOH À10% H2O
À0.2% H3PO4). SR-9g RT/SS-9g RT = 5.30 min/5.65 min.
5. Bowers, C. Y.; Momany, F. A.; Reynolds, G. A.; Hong,
A. Endocrinology 1984, 114, 1537.
6. (a) DeVita, R. J.; Schoen, W. R.; Fischer, M. H.;
Fontier, A. J.; Pisano, J. M.; Wyvratt, M. J.; Cheng, K.;
Chan, W.-S.; Butler, B. S.; Hickey, G. J.; Jacks, T. M.;
Smith, R. G. Bioorg. Med. Chem. Lett. 1994, 4, 2229;
(b) Patchett, A. A.; Nargund, R. P.; Tata, J. R.; Chen,
M.-H.; Barakat, 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. Proc. Natl. Acad. Sci. U.S.A. 1995, 92, 7001.
7. Kojima, M.; Hosoda, H.; Date, Y. Nature 1999, 402, 656.