3-pyridylethanolamines: Potent and selective human β3 adrenergic receptor agonists

Bioorganic and Medicinal Chemistry Letters

Volumn 8, Issue 21, 1998, Pages 3087-3092

  Naylor, Elizabeth M ^a   Colandrea, Vincent J ^a   Candelore, Mari R ^a   Cascieri, Margaret A ^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   Strader, Catherine D ^a   Tota, Laurie ^a   Wang, Pei Ran ^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 757793; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ARTICLE; DRUG EFFECT; DRUG POTENCY; DRUG RECEPTOR BINDING; DRUG SELECTIVITY; HUMAN; LIPOLYSIS; NONHUMAN; RECEPTOR AFFINITY; RHESUS MONKEY; STRUCTURE ACTIVITY RELATION;

ADRENERGIC BETA-AGONISTS; ANIMALS; DOGS; HUMANS; MACACA MULATTA; MALE; RECEPTORS, ADRENERGIC, BETA; RECEPTORS, ADRENERGIC, BETA-3; STRUCTURE-ACTIVITY RELATIONSHIP; SULFONAMIDES;

ANIMALIA; MACACA MULATTA;

EID: 0000649845     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(98)00571-X     Document Type: Article

References (20)

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2. 2. For recent reviews see: Lowell, B. B.; Flier, J. S. Annu. Rev. Med. 1997, 48, 307; Strosberg, A. D.; Pietri-Rouxel, F. Trends Pharmacol. Sci. 1996, 206, 373; Arch, J. R. S.; Wilson, S. Int. J. Obesity 1996, 20, 191.
3. 2. For recent reviews see: Lowell, B. B.; Flier, J. S. Annu. Rev. Med. 1997, 48, 307; Strosberg, A. D.; Pietri-Rouxel, F. Trends Pharmacol. Sci. 1996, 206, 373; Arch, J. R. S.; Wilson, S. Int. J. Obesity 1996, 20, 191.
4. 3. For reviews see: Dow, R. L. Exp. Opin. Invest. Drugs 1997, 6, 1811; Claus, T. H.; Bloom, J. D. Ann. Rep. Med. Chem. 1995, 30, 189.
5. 3. For reviews see: Dow, R. L. Exp. Opin. Invest. Drugs 1997, 6, 1811; Claus, T. H.; Bloom, J. D. Ann. Rep. Med. Chem. 1995, 30, 189.
6. 4. Arch, J. R. S; Ainsworth, A. T.; Cawthorne, M. A.; Piercy, V.; Sennitt, M. V.; Thody, V. E.; Wilson, C.; Wilson, S. Nature 1984, 309, 163.
7. 5. Liggett, S. B. Mol. Pharmacol. 1992, 42, 634.
8. 125I-iodocyanopindolol binding, respectively.
9. 125I-iodocyanopindolol binding, respectively.
10. 7. 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.
11. 8. 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.
12. 9. 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. J.; 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.
13. 10. 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. J.; 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.
14. 11. Presented in part at the 26th National Medicinal Chemistry Symposium, Richmond, VA, June 1998; Abstract D29.
15. 12. The phenethanolamines 3a and 3-chloro analogs 3b were synthesized from the commercially available chiral epoxides in a similar manner to that reported for the aryloxypropanolamines (see ref 7). Epoxide opening with p-aminophenethylamine was followed by selective Boc-protection of the resultant secondary amine. Treatment with the appropriate sulfonyl chloride and deprotection with TFA afforded the desired sulfonamides 3a and 3b. (matrix presented)
16. 3 AR agonist activity examined. In each case, in line with expectation, the R isomer was 5-190 fold more potent than the respective S isomer. All final compounds were characterized by NMR, mass spectrometry and HPLC. For experimental details see: Fisher, M. H.; Naylor, E. M.; Weber, A. E. U.S. Patent 5 541 197, 1996.
17. 14. Personal communication from Dr. Sander G. Mills.
18. 1H NMR spectrum. (matrix presented)
19. 16. The 4-ureidobenzenesulfonyl chlorides were prepared either by treatment of the phenyl urea with chlorosulfonic acid or by addition of the amine to 4-(chlorosulfonyl)phenyl isocyanate. The 4-carbamoylbenzenesulfonyl chlorides were synthesized by addition of the alcohol to 4-(chlorosulfonyl)phenyl isocyanate. The 4-amidobenzenesulfonyl chlorides were prepared by treatment of the 4-amidobenzene with chlorosulfonic acid.
20. 17. Male lean rhesus monkeys (n = 3) were fasted overnight and administered ketamine (10 mg/kg, im) for induction of anesthesia. Catheters were placed in the cephalic vein and femoral artery for intravenous drug administration and measurement of arterial pressure and heart rate. ECG leads were also attached for monitoring Lead II ECG and heart rate. While monitoring the cardiovascular parameters, Nembutal (20-25 mg/kg, iv) was given over 10 min for anesthesia. Heart rate was monitored for approximately 30 min until stable baseline values were obtained, at which time animals were administered a series of bolus doses of test compound in a vehicle consisting of 10% aqueous citric acid solution (10 mM), 30% PEG400, 60% saline. Bolus doses were separated by an interval of 15 min. Blood samples (2 mL) were collected from the femoral artery one min prior to the administration of compound and 14 min after each bolus dose. Serum glycerol was measured using an enzymatic colorimetric assay. After completion of the series of bolus doses of test compound, animals were administered an infusion of isoproterenol (100 μg/kg) over 15 min to elicit a maximal increase in serum glycerol.