BMS-187257, a potent, selective, and novel heterocyclic β3 adrenergic receptor agonist

Bioorganic and Medicinal Chemistry Letters

Volumn 6, Issue 19, 1996, Pages 2253-2258

  Fisher, Liesl G ^a,b   Sher, Philip M ^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 HYDROXY 3 PHENOXYPROPYL)AMINO]ETHOXY]PHENOXYACETIC ACID; 4 [2 [[2 (3 CHLOROPHENYL) 2 HYDROXYETHYL]AMINO]PROPYL]PHENOXYACETIC ACID; ADENYLATE CYCLASE; BETA ADRENERGIC RECEPTOR; BETA ADRENERGIC RECEPTOR STIMULATING AGENT; BMS 1827257; RECEPTOR SUBTYPE; THIAZOLE DERIVATIVE; UNCLASSIFIED DRUG;

ANIMAL CELL; ARTICLE; CELL MEMBRANE; CHO CELL; CONTROLLED STUDY; DRUG RECEPTOR BINDING; DRUG SYNTHESIS; ENZYME ACTIVATION; GENE EXPRESSION; GENE TRANSFER; HUMAN; NONHUMAN;

EID: 0030575622     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/0960-894X(96)00417-9     Document Type: Article

References (22)

1. 2. Sher, P. M. U.S. Patent 5321036, 6/14/94. This patent provides the syntheses of all of the heterocyclic compounds described herein (3a-b and 4a-c). As depicted, 3a-b are mixtures of R,R and S,R stereoisomers (1:1) and 4a-c are single S,R stereoisomers.
2. 3. (a) Arch, J. R. S.; Ainsworth, A. T.; Cawthorne, M. A.; Piercy, V.; Sennitt, M. V.; Thody, V. E.; Wilson, C.; Wilson, S. Nature (London) 1984, 309, 163.
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7. 7. Howe, R.; Rao, B. S.; Holloway, B. R.; Stribling, D. J. Med. Chem. 1992, 35, 1751. ICI 215001 is the active (S) isomer component of ICI 201651 (a racemate).
8. 8. See also Alig, L.; Müller, M. U.S. Patents 5064863, 4871755, 4743604, 4652679, and 4585796. These workers reported replacement of the right-hand aryl ring with a thiophene. This modification led to active compounds, but because biological data was reported at only a single dose in vivo, it was impossible to gain an understanding of structure-activity relationships at the receptor level. However, this indication that the right-hand aryl ring might be replaced by a heterocycle, coupled with the novelty and synthetic accessiblity of our thiazole analogs, prompted the study described herein.
9. 9. Tate, K. M.; Briend-Sutren, M.-M.; Emorine, L. J.; Delavier-Klutchko, C.; Marullo, S.; Strosberg, A. D. Eur. J. Biochem. 1991, 196, 357. Blin, N.; Camoin, L.; Maigret, B.; Strosberg, A. D. Mol. Pharm. 1993, 44, 1094. See also reference 11.
10. 9. Tate, K. M.; Briend-Sutren, M.-M.; Emorine, L. J.; Delavier-Klutchko, C.; Marullo, S.; Strosberg, A. D. Eur. J. Biochem. 1991, 196, 357. Blin, N.; Camoin, L.; Maigret, B.; Strosberg, A. D. Mol. Pharm. 1993, 44, 1094. See also reference 11.
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12. 3 - CHO cell membranes, rather than whole cells, were used: Fève, B.; Emorine, L. J.; Lasnier, F.; Blin, N.; Baude, B.; Nahmias, C.; Strosberg, A. D.; Pairault, J. Biol. Chem. 1991, 266, 20329. Liggett, S. B. Mol. Pharm. 1992, 42, 634. 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.
13. 3 - CHO cell membranes, rather than whole cells, were used: Fève, B.; Emorine, L. J.; Lasnier, F.; Blin, N.; Baude, B.; Nahmias, C.; Strosberg, A. D.; Pairault, J. Biol. Chem. 1991, 266, 20329. Liggett, S. B. Mol. Pharm. 1992, 42, 634. 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.
14. 3 - CHO cell membranes, rather than whole cells, were used: Fève, B.; Emorine, L. J.; Lasnier, F.; Blin, N.; Baude, B.; Nahmias, C.; Strosberg, A. D.; Pairault, J. Biol. Chem. 1991, 266, 20329. Liggett, S. B. Mol. Pharm. 1992, 42, 634. 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.
15. 3 - CHO cell membranes, rather than whole cells, were used: Fève, B.; Emorine, L. J.; Lasnier, F.; Blin, N.; Baude, B.; Nahmias, C.; Strosberg, A. D.; Pairault, J. Biol. Chem. 1991, 266, 20329. Liggett, S. B. Mol. Pharm. 1992, 42, 634. 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.
16. 12. Huckstep, M.; Taylor, R. J. K.; Caton, M. P. L. Synthesis 1982, 881.
17. 13. Poittevin, A.; Torelli, V. U.S. Patent 4053618, 10/11/77.
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19. 10 in excess diphenyl ether at 165-170 °C. See Lajoie, G.; Lépine, F.; Maziak, L.; Belleau, B. Tetrahedron Lett. 1983, 24, 3815. This reagent gave higher yields than Lawesson's reagent.
20. 16. Recrystallization of this reagent from ethanol increased its optical purity to over 99% from approximately 92% as purchased (Aldrich). The reaction with phenoxide proceeded with a loss of only 0.2% ee. See Klunder, J. M.; Onami, T.; Sharpless, K. B. J. Org. Chem. 1989, 54, 1295.
21. 17. Spectral data were fully consistent with the structures depicted.
22. 7 Aryloxypropanolamines 4a-c bear the same structural relationship to the carboxylic acid of 11 (its presumed active metabolite) that arylethanolamines 3a-b bear to BRL 37344. (formula presented)