Carboxyl-promoted enhancement of selectivity for the β3 adrenergic receptor. Negative charge of the sulfonic acid BMS-187413 introduces β3 binding selectivity

Bioorganic and Medicinal Chemistry Letters

Volumn 7, Issue 12, 1997, Pages 1583-1588

  Sher, Philip M ^a   Mathur, Arvind ^a   Fisher, Liesl G ^a,b   Wu, Gang ^a   Skwish, Stephen ^a   Michel, Inge M ^a   Seiler, Steven M ^a   Dickinson, Kenneth E J ^a  

^a BRISTOL MYERS SQUIBB   (United States)

^b RUTGERS ROBERT WOOD JOHNSON MEDICAL SCHOOL   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

4 [2 [[2 (3 CHLOROPHENYL) 2 HYDROXYETHYL]AMINO]PROPYL]PHENOXYACETIC ACID; ADRENERGIC RECEPTOR; BETA 3 ADRENERGIC RECEPTOR; BMS 187431; PHENETHYLAMINE DERIVATIVE; RECEPTOR SUBTYPE; UNCLASSIFIED DRUG;

ANIMAL CELL; ARTICLE; BINDING AFFINITY; CHO CELL; CONTROLLED STUDY; DRUG RECEPTOR BINDING; DRUG SYNTHESIS; GENE EXPRESSION; HUMAN; IN VITRO STUDY; NONHUMAN; STRUCTURE ACTIVITY RELATION;

EID: 0030950052     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(97)00266-7     Document Type: Article

References (40)

1. Sher, P. M.; Fisher, L. G.; Skwish, S.; Michel, I. M.; Seiler, S. M.; Washburn, W. N.; Dickinson, K. E. J. Med. Chem. Res., in press.
2. Duckworth, D. M. US Patent 4 382 958, 1983; Chem. Abstr. 1982, 97, 162563.
3. Duckworth, D. M. US Patent 4 382 958, 1983; Chem. Abstr. 1982, 97, 162563.
4. Ainsworth, A. T.; Smith, D. G. US Patent 4 338 333, 1982; Chem. Abstr. 1981, 95, 61726.
5. Ainsworth, A. T.; Smith, D. G. US Patent 4 338 333, 1982; Chem. Abstr. 1981, 95, 61726.
6. Beeley, L. J.; Smith, R. A. G. World Patent Application 94/24090, 1994; Chem. Abstr. 1995, 122, 31110.
7. Beeley, L. J.; Smith, R. A. G. World Patent Application 94/24090, 1994; Chem. Abstr. 1995, 122, 31110.
8. Sher, P. M.; Mathur, A. US Patent 5 491 134, 1996; Chem. Abstr. 1996, 124, 343660.
9. Sher, P. M.; Mathur, A. US Patent 5 491 134, 1996; Chem. Abstr. 1996, 124, 343660.
10. Beeley, L. J.; Berge, J. M. World Patent Application 95/07284, 1995; Chem. Abstr. 1995, 123, 144275.
11. Beeley, L. J.; Berge, J. M. World Patent Application 95/07284, 1995; Chem. Abstr. 1995, 123, 144275.
12. Beeley, L. J.; Berge, J. M.; Jarvest, R. L. World Patent Application 94/02493, 1994; Chem. Abstr. 1994, 120, 323858.
13. Beeley, L. J.; Berge, J. M.; Jarvest, R. L. World Patent Application 94/02493, 1994; Chem. Abstr. 1994, 120, 323858.
14. (a) Tate, K. M.; Briend-Sutren, M.-M.; Emorine, L. J.; Delavier-Klutchko, C.; Marullo, S.; Strosberg, A. D. Eur. J. Biochem. 1991, 196, 357.
15. (b) Blin, N.; Camoin, L.; Maigret, B.; Strosberg, A. D. Mol. Pharm. 1993, 44, 1094. See also references 19a, 19b, 19c, and 19e.
16. Salomon, Y.; Londos, C.; Rodbell, M. Anal. Biochem. 1974, 58, 541.
17. Cantello, B. C. C.; Smith, S. A. Drugs of the Future 1991, 16, 797.
18. Nichols, D. E.; Barfknecht, C. F.; Rusterholz, D. B.; Benington, F.; Morin, R. D. J. Med. Chem. 1973, 16, 480.
19. Atkins, R. K.; Frazier, J.; Moore, L. L.; Weigel, L. O. Tetrahedron Lett. 1986, 27, 2451.
20. Petigara, R. B.; Yale, H. L. J. Het. Chem. 1974, 11, 331.
21. Moedritzer, K. J. Am. Chem. Soc. 1961, 83, 4381.
22. Lee, S-F.; Henrick, C. A. US Patent 4 536 355, 1985; Chem. Abstr. 1986, 104, 225044.
23. Lee, S-F.; Henrick, C. A. US Patent 4 536 355, 1985; Chem. Abstr. 1986, 104, 225044.
24. Takemura, K. H.; Pulickal, M.; Hoff, F. O. J. Org. Chem. 1971, 36, 3646.
25. Spectral data were fully consistent with the structures depicted.
26. 3 - CHO cell adenylyl cyclase assays, particularly where cell membranes, rather than whole cells, were used. See (a) Fève, B.; Emorine, L. J.; Lasnier, F.; Blin, N.; Baude, B.; Nahmias, C.; Strosberg, A. D.; Pairault, J. Biol. Chem. 1991, 266, 20329.
27. (b) Liggett, S. B. Mol. Pharm. 1992, 42, 634.
28. Granneman, J. G.; Lahners, K. N.; Chaudry, A. Mol. Pharm. 1993, 44, 264. Arch, J. R. S.; Wilson, S. Int. J. Obesity 1996, 20, 191.
29. Granneman, J. G.; Lahners, K. N.; Chaudry, A. Mol. Pharm. 1993, 44, 264. Arch, J. R. S.; Wilson, S. Int. J. Obesity 1996, 20, 191.
30. Dolan, J. A.; Muenkel, H. A.; Burns, M. G.; Pellegrino, S. M.; Fraser, C. M.; Pietri, F.; Strosberg, A. D.; Largis, E. E.; Dutia, M. D.; Bloom, J. D.; Bass, A. S.; Tanikella, T. K.; Cobuzzi, A.; Lai, F. M.; Claus, T. H. J. Pharm. Exp. Ther. 1994, 269, 1000.
31. (e) Wilson, S.; Chambers, J. K.; Park, J. E.; Ladurner, A.; Cronk, D. W.; Chapman, C. G.; Kallender, H.; Browne, M. J.; Murphy, G. J.; Young, P. W. J. Pharm. Exp. Ther. 1996, 279, 214.
32. It is likely that the hydroxamic acid is largely undeprotonated at the pH of the assay buffer: Challis, B. C.; Challis, J. A. In Comprehensive Organic Chemistry; Sutherland, I. O., Ed.; Pergamon: New York, 1979; Vol 2, pp 957-1065. Bauer, L.; Exner, O. Angew. Chem., Int. Ed. Engl. 1974, 13, 376. Monzyk, B.; Crumbliss, A. L. J. Org. Chem. 1980, 45, 4670.
33. It is likely that the hydroxamic acid is largely undeprotonated at the pH of the assay buffer: Challis, B. C.; Challis, J. A. In Comprehensive Organic Chemistry; Sutherland, I. O., Ed.; Pergamon: New York, 1979; Vol 2, pp 957-1065. Bauer, L.; Exner, O. Angew. Chem., Int. Ed. Engl. 1974, 13, 376. Monzyk, B.; Crumbliss, A. L. J. Org. Chem. 1980, 45, 4670.
34. It is likely that the hydroxamic acid is largely undeprotonated at the pH of the assay buffer: Challis, B. C.; Challis, J. A. In Comprehensive Organic Chemistry; Sutherland, I. O., Ed.; Pergamon: New York, 1979; Vol 2, pp 957-1065. Bauer, L.; Exner, O. Angew. Chem., Int. Ed. Engl. 1974, 13, 376. Monzyk, B.; Crumbliss, A. L. J. Org. Chem. 1980, 45, 4670.
35. th American Chemical Society National Meeting, San Diego, CA, MEDI 230, March 13-17, 1994.
36. Malonic acids, especially α-aryloxymalonic acids, are doubly deprotonated at the pH of the assay buffer (pH 7.4). See Roberts, S. M. In Comprehensive Organic Chemistry; Sutherland, I. O., Ed.; Pergamon: New York, 1979; Vol 2, pp 739-778.
37. 3 binding potency.
38. We note that some of the compounds tested herein were single R,R isomers and others were 1:1 mixtures of R,R isomers with either S,R or S,S isomers. We believe that our analyses in which mixtures and single isomers are considered together are, nevertheless, valid for the following reasons. Based on general SAR of β AR ligands and the specific SAR of Beecham's compounds, we believe that only the R,R isomers of the compounds described in this paper are pharmacologically relevant. See, respectively (a) Ruffolo, R. R., Jr. Drug Design and Discovery 1993, 9, 351.
39. (b) Muzzin, P.; Boss, O.; Mathis, N.; Revelli, J.-P.; Giacobino, J.-P.; Willcocks, K.; Badman, G. T.; Cantello, B. C. C.; Hindley, R. M.; Cawthorne, M. A. Mol. Pharm. 1994, 46, 357.
40. Oriowo, M. A.; Chapman, H.; Kirkham, D. M.; Sennitt, M. V.; Ruffolo, R. R., Jr.; Cawthorne, M. A. J. Pharm. Exp. Ther. 1996, 277, 22. S,S and S,R isomers in mixtures with R,R isomers can be considered inert. Compounds described herein which are 1:1 mixtures ought to have exhibited binding constants twofold higher than those that would have been measured had the pure R,R isomers been tested. (Reference 24c clearly shows in several assays that BRL 37344 (1), a R,R./S,S racemate, is half as active as its R,R component isomer, and that the R,S isomer, the S,R isomer, and the S,S isomer are all essentially inert.) Since this argument applies to binding to all β ARs, binding selectivities observed for the mixtures are the same as those that would have been measured with pure R,R isomers. Correction for the distortion of binding constants, by adjusting the binding constants of some compounds by a factor of 2, does not alter our overall interpretation of the data.