L-770,644: A potent and selective human β3 adrenergic receptor agonist with improved oral bioavailability

Bioorganic and Medicinal Chemistry Letters

Volumn 9, Issue 9, 1999, Pages 1251-1254

  Shih, Thomas L ^a   Candelore, Mari R ^a   Cascieri, Margaret A ^a   Chiu, Shuet Hing L ^a   Colwell Jr , Lawrence F ^a   Deng, Liping ^a   Feeney, William P ^a   Forrest, Michael J ^a   Hom, Gary J ^a   Macintyre, D Euan ^a   Miller, Randall R ^a   Stearns, Ralph A ^a   Strader, Catherine D ^a   Tota, Laurie ^a   Wyvratt, Matthew J ^a   Fisher, Michael H ^a   Weber, Ann E ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

BETA 3 ADRENERGIC RECEPTOR STIMULATING AGENT; L 764646; L 766892; L 770664; UNCLASSIFIED DRUG;

ADRENERGIC ACTIVITY; ANIMAL EXPERIMENT; ARTICLE; DRUG BIOAVAILABILITY; DRUG METABOLISM; DRUG RECEPTOR BINDING; DRUG SELECTIVITY; DRUG STRUCTURE; DRUG SYNTHESIS; GLYCEROL BLOOD LEVEL; MALE; NONHUMAN; ORAL DRUG ADMINISTRATION; RAT;

ADMINISTRATION, ORAL; ADRENERGIC BETA-AGONISTS; ANIMALS; BIOLOGICAL AVAILABILITY; DOGS; HUMANS; INHIBITORY CONCENTRATION 50; KINETICS; RATS; SULFONAMIDES; TETRAZOLES;

EID: 0033519248     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(99)00182-1     Document Type: Article

References (18)

1. Present address: Schering Plough Research Institute, 2015 Galloping Hill Rd, Kenilworth, NJ 07033.
2. For recent reviews see: (a) Weber, A. E. Ann. Rep. Med. Chem. 1998, 33, 193;
3. (b) Dow, R. L. Exp. Opin. Invest. Drugs 1997, 6, 1811;
4. (c) Lowell, B. B.; Flier, J. S. Annu. Rev. Med. 1997, 48, 307;
5. (d) Arch, J. R. S.; Wilson, S. Int. J. Obesity 1996, 20, 191;
6. (e) Himms-Hagen, J.; Danforth, E. Curr. Opin. Endocrin. Diabetes 1996, 3, 59.
7. Fisher, M. H.; Amend, A. M.; Bach, T. J.; Barker, J. M.; Brady, E. J.; Candelore, M. R.; Carroll, D.; Cascieri, M. A.; Chiu, S-H. L.: Deng, L.; Forrest, M. J.; Hegarty-Friscino, B.; Guan, X.-M.; Hom, G. H.; Hutchins, J. E.; Kelly, L. J.; Mathvink, R. J.; Metzger, J. M.; Miller, R. R.; Ok, H.O.; Parmee, E. R.; Saperstein, R.; Strader, C. D.; Stearns, R. A.; Thompson, G. M.; Tota, L.; Vicario, P. P.; Weber, A. E.; Woods, J. W.; Wyvratt, M. J.; Zafian, P. T.; MacIntyre, D. E. J. Clin. Invest. 1998, 101, 2387.
8. Weber, A. E.; Ok, H. O.; Alvaro, R. F.; Candelore, M. R.; Cascieri, M. A.; Chiu, S-H. L.; Deng, L.; Forrest, M. J.; Hom, G. H.; Hutchins, J. E.; Kao, J.; MacIntyre, D.E.; Mathvink, R. J.; McLoughlin, D.; Miller, R.R., Newbold, R. C.; Olah, T. V.; Parmee, E. R.; Perkins L.; Stearns, R. A.; Strader, C.D.; Szumiloski, J.; Tang, Y.S.; Tota, L.; Vicario, P. P.; Wyvratt, M. J.; Fisher, M. H. Bioorg. Med. Chem. Lett. 1998, 8, 2111.
9. Naylor, E. M.; Colandrea, V. J.; Candelore, M. R.; Cascieri, M. A.; Colwell, L. F.; Deng, L.; Feeney, W. P.; Forrest, M. J.; Hom, G. H.; MacIntyre, D.E.; Strader, C.D.; Tota, L.; Wang, P.-R.; Wyvratt, M. J.; Fisher, M. H.; Weber, A. E. Bioorg. Med. Chem. Lett. 1998, 8, 3087.
10. Parmee, E. R.; Naylor, E. M.; Colandrea, Perkins, L.; V.J.; Candelore, M. R.; Cascieri, M. A.; Deng, L.; Feeney, W. P.; Forrest, M. J.; Hom, G. J.; MacIntyre, D. E.; Miller, R. R.; Ok, H. O.; Stearns, R. A.; Strader, C. D.; Tota, L.; Wyvratt, M. J.; Fisher, M. H.; Weber, A. E. Bioorg. Med. Chem. Lett. 1999, 9, 749.
11. Naylor, E. M.; Parmee, E. R.; Colandrea, V. J.; Perkins, L.; Brockunier, L.; Candelore, M. R.; Cascieri, M. A.; Colwell, L. F. ; Deng, L.; Feeney, W. P.; Forrest, M. J.; Hom, G. J.; MacIntyre, D. E.; Strader, C. D.; Tota, L.; Wang, P.-R.; Wyvratt, M. J.; Fisher, M. F.; Weber, A. E. Bioorg. Med. Chem. Lett. 1999, 9, 755.
12. All final compounds were characterized by NMR, mass spectrometry and HPLC. For experimental details see: Fisher, M. H.; Naylor, E. M.; Ok, D.; Weber, A. E.; Shih, T.; Ok, H. U.S. Patent 5 561 142, 1996; Chem. Abstr. 1996, 125, 275666.
13. Horwitz, J. P.; Fisher, B. E.; Tomasewski, A. J. J. Amer. Chem. Soc. 1959, 81, 3076.
14. Hoffman, R. V. Org. Synth. 1981, 60, 121.
15. 125I-iodocyanopindolol binding, repectively.
16. 125I-iodocyanopindolol binding, repectively.
17. Compounds were dosed orally at 10 mg/kg as a solution in 0.1 M aqueous citric acid, and intraveneously at 3 mg/kg in a vehicle consisting of polyethylene glycol 400 (PEG400), ethanol and normal saline. Blood samples were collected prior to dosing and at 5 (iv only), 15 and 30 min and 1, 2, 6, 8, and 24 h post dosing, for determination of plasma glycerol concentrations using a Sigma Triglyceride (GPO-TRINDER) assay kit and plasma drug concentrations by LC/MS/MS.
18. 3