Optimization of 1H-tetrazole-1-alkanenitriles as potent orally bioavailable growth hormone secretagogues

Bioorganic and Medicinal Chemistry Letters

Volumn 18, Issue 6, 2008, Pages 2067-2072

  Hernández, Andrés S ^a   Swartz, Stephen G ^a   Slusarchyk, Dorothy ^a   Yan, Mujing ^a   Seethala, R Krishna ^a   Sleph, Paul ^a   Grover, Gary ^a   Dickinson, Kenneth ^a   Giupponi, Leah ^a   Harper, Timothy W ^b   Humphreys, W Griffith ^b   Longhi, Daniel A ^a   Flynn, Neil ^a   Murphy, Brian J ^a   Gordon, David A ^a   Biller, Scott A ^a   Robl, Jeffrey A ^a   Tino, Joseph A ^a  

^a BRISTOL MYERS SQUIBB   (United States)

^b BRISTOL MYERS SQUIBB PHARMACEUTICAL RESEARCH INSTITUTE   (United States)

Author keywords

Enantiospecific synthesis; Growth hormone secretagogues; Tetrazole

Indexed keywords

GROWTH HORMONE SECRETAGOGUE; LEAD; NITRILE;

ALKYLATION; ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; CHEMICAL MODIFICATION; CONTROLLED STUDY; DOG; DRUG POTENCY; GROWTH HORMONE RELEASE; IC 50; IN VITRO STUDY; LIPOPHILICITY; MOLECULAR INTERACTION; NONHUMAN; PHYSICAL CHEMISTRY; RAT; REACTION OPTIMIZATION; STRUCTURE ACTIVITY RELATION;

ADMINISTRATION, ORAL; ANIMALS; BIOLOGICAL AVAILABILITY; CYTOCHROME P-450 ENZYME SYSTEM; DOGS; GROWTH HORMONE; MAGNETIC RESONANCE SPECTROSCOPY; MOLECULAR STRUCTURE; NITRILES; PITUITARY GLAND; RATS; STRUCTURE-ACTIVITY RELATIONSHIP; TETRAZOLES;

CANIS FAMILIARIS; RATTUS;

EID: 40749118020     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2008.01.100     Document Type: Article

References (18)

1. Rivier J., Spiess J., Thorner M., and Vale W. Nature 300 (1982) 276
2. Bowers C.Y. In: Bercu B.B., and Walker R.F. (Eds). Growth Hormone Secretagogues (1996), Springer-Verlag, New York 9-28
3. Bowers C.Y., Reynolds G.A., Durham D., Barrera C.M., Pezzoli S.S., and Thorner M.O. J. Clin. Endocrinol. Metab. 70 (1990) 975
4. Reichlin S., Saperstain R., Jackson I.M.D., Boyd A.E., and Patel Y. Ann. Rev. Physiol. 38 (1976) 389
5. 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., and Van der Ploeg L.H.T. Science 273 (1996) 974
6. Bowers C.Y., Momany F.A., Reynolds G.A., and Hong A. Endocrinology 114 (1984) 1537
7. 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., and Smith R.G. Bioorg. Med. Chem. Lett. 4 (1994) 2229
8. 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., and Smith R.G. Proc. Natl. Acad. Sci. U.S.A. 92 (1995) 7001
9. Kojima M., Hosoda H., and Date Y. Nature 402 (1999) 656
10. Carpino P.A. Exp. Opin. Ther. Patents 12 (2002) 1599
11. Dodge J.A., and Heiman M.L. Annu. Rep. Med. Chem. 38 (2003) 81
12. 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., and Thompson D.D. Endocrine 14 (2001) 437
13. 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., and Cutler Jr. G.B. Drug Dev. Res. 49 (2000) 260
14. Lugar C.W., Clay M.P., Lindstrom T.D., Woodson A.L., Smiley D., Heiman M.L., and Dodge J.A. Bioorg. Med. Chem. Lett. 14 (2004) 5873
15. Hernández 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., and Tino J.A. Bioorg. Med. Chem. Lett. 17 (2007) 5928
16. 1H NMR easily distinguished between the 1H and 2H isomers by comparison of the Δδ between the methyls of the 2-aminoisobutyric fragment. The Δδ is significantly larger in the 1H isomer than in the 2H isomer.
17. 250 of MK-677 is 0.46 μmol/kg.
18. 4). SR-9g RT/SS-9g RT = 5.30 min/5.65 min.