3-pyridyloxypropanolamine agonists of the β3 adrenergic receptor with improved pharmacokinetic properties

Bioorganic and Medicinal Chemistry Letters

Volumn 8, Issue 16, 1998, Pages 2111-2116

  Weber, Ann E ^a   Ok, Hyun O ^a   Alvaro, Raul F ^a   Candelore, Mari R ^a   Cascieri, Margaret A ^a   Chiu, Shuet Hing L ^a   Deng, Liping ^a   Forrest, Michael J ^a   Hom, Gary J ^a   Hutchins, Jennifer E ^a   Kao, John ^a   MacIntyre, D Euan ^a   Mathvink, Robert J ^a   McLoughlin, Debra ^a   Miller, Randall R ^a   Newbold, Ronald C ^a   Olah, Timothy V ^a   Parmee, Emma R ^a   Perkins, Leroy ^a   Stearns, Ralph A ^a   Strader, Catherine D ^a   Szumiloski, John ^a   Tang, Yui S ^a   Tola, Laurie ^a   Vicario, Pasquale P ^a   Wyvratt, Matthew J ^a   Fisher, Michael H ^a   more..

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

(2 PYRIDYLOXY)PROPANOLAMINE DERIVATIVE; BETA 3 ADRENERGIC RECEPTOR STIMULATING AGENT; L 749372; L 750355; PROPANOLAMINE DERIVATIVE; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ARTICLE; DOG; DRUG BIOAVAILABILITY; DRUG EFFECT; DRUG RECEPTOR BINDING; DRUG SYNTHESIS; HEART RATE; LIPOLYSIS; NONHUMAN; OBESITY; RHESUS MONKEY;

ADRENERGIC BETA-AGONISTS; ANIMALS; BINDING, COMPETITIVE; BIOLOGICAL AVAILABILITY; DOGS; HUMANS; KINETICS; LIPOLYSIS; MACACA MULATTA; MOLECULAR STRUCTURE; PROPANOLAMINES; PYRIDINES; RECEPTORS, ADRENERGIC, BETA; RECEPTORS, ADRENERGIC, BETA-3; STRUCTURE-ACTIVITY RELATIONSHIP; SULFONAMIDES;

ANIMALIA; CANIS FAMILIARIS; MACACA MULATTA;

EID: 0032544167     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(98)00381-3     Document Type: Article

References (16)

1. 1. Present addresses: (a) Wyeth-Ayerst Research, Princeton, NJ 08543; (b) Schering Plough Research Institute, Kenilworth, NJ 07033.
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6. (e) Claus, T. H.; Bloom, J. D. Ann. Rep. Med. Chem. 1995, 30, 189.
7. 3. Weber, A. E.; Mathvink, R. J.; Perkins, L.; Hutchins, J. E.; Candelore, M. R.; Tota, L.; Strader, C. D.; Wyvratt, M. J.; Fisher, M. H. Bioorg. Med. Chem. Lett. 1998, 8, 1101.
8. 4. Parmee, E. R.; Ok, H. O.; Candelore, M. R.; Tota, L.; Deng, L.; Strader, C. D.; Wyvratt, M. J.; Fisher, M. H.; Weber, A. E. Bioorg. Med. Chem. Lett. 1998, 8, 1107.
9. 5. 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.
10. 6. Presented in part at the 213th National Meeting of the American Chemical Society, San Francisco, CA, April 1997; Abstract MEDI0168.
11. 7. Synthesized from aniline i (Ref. 3) by treatment with W-bromosuccinimide in benzene to give ii, followed by acylation with the appropriate sulfonyl chloride, treatment with tritium gas over palladium on calcium carbonate, and deprotection with methanolic hydrogen chloride: (equation presented)
12. 8. For experimental details see: Fisher, M. H.; Mathvink, R. J.; Ok, H.O.; Parmee, E. R.; Weber, A. E. U. S. Patent 5 451 677, 1995; Chem. Abstr. 1996, 124, 116877.
13. 9. Granneman, J. G.; Lahners, K. N.; Rao, D. D. Mol. Pharmacol. 1992, 42, 964.
14. 125I-iodocyanopindolol binding, repectively.
15. 125I-iodocyanopindolol binding, repectively.
16. 11. See Ref. 5 for experimental details. Due to the small signal to noise ratio in conscious animals, this assay is run in anesthetized rhesus, which effectively precludes oral dosing. Briefly, male lean rhesus monkeys (n = 3) were fasted for 24 h and anesthetized. An intraveneous catheter was placed in a saphenous vein for the administration of test compounds and ECG leads were connected for the continuous measurement of heart rate. Heart rate was monitored for approximately 30 minutes until stable baseline values were obtained, at which time animals were administered a series of rising dose infusions (0.1 mL/min) of test compound over a 15-min period. Infusion periods were separated by an interval of approximately 20 sec. Blood samples (2 mL) were collected from the femoral artery 1 min prior to the initiation of infusions and 14 min into each infusion period. Serum glycerol was measured using an enzymatic colorimetric assay.