D. Beattie et al. / Bioorg. Med. Chem. Lett. 20 (2010) 5302–5307
5307
Bioorg. Med. Chem. Lett. 2008, 18, 1280; (f) Brown, A. D.; Bunnage, M. E.;
Glossop, P. A.; Holbrook, M.; Jones, R. D.; Lane, C. A. L.; Lewthwaite, R. A.;
Mantell, S.; Perros-Huguet, C.; Price, D. A.; Webster, R. Bioorg. Med. Chem. Lett.
2007, 17, 6188; (g) Brown, A. D.; Bunnage, M. E.; Glossop, P. A.; James, K.; Jones,
R.; Lane, C. A. L.; Lewthwaite, R. A.; Mantell, S.; Perros-Huguet, C.; Price, D. A.;
Trevethick, M.; Webster, R. Bioorg. Med. Chem. Lett. 2007, 17, 4012.
5. Beier, J.; Gillissen, A.; Beeh, K.-M. Atemweg. Lungenkrank. 2009, 35, 521.
6. Waldeck, B. J. J. Allergy Clin. Immunol. 1999, 103, 742.
terol (Clint 186
lised than indacaterol (Clint 226
l
l/min/mg) and 77% being more rapidly metabo-
ll/min/mg). In terms of the origi-
nal hypothesis, the approach had satisfied the initial objective by
providing a large proportion of the analogues with high suscepti-
bilities for undergoing glucuronidation. However, when a diverse
set of amino substituents are considered it is clear that changes
to this portion of the molecule also make a significant contribution
to modulating the rates of glucuronidation observed within the 4-
hydroxybenzothiazolone series 1. Analysis of the overall data iden-
tified groups of analogues of particular interest consistently exhib-
iting increased glucuronidation rates compared to formoterol and
indacaterol, for example: b-phenylethylamines, as represented by
7. Matthys, H.; Medizinische, K. Respiration 2001, 68, 432.
8. White, M. V.; Sander, N. J. Allergy Clin. Immunol. 1999, 104, 47.
9. Byron, P. R. Proc. Am. Thorac. Soc. 2004, 1, 321.
10. (a) Baur, F.; Beattie, D.; Beer, D.; Bentley, D.; Bradley, M.; Bruce, I.; Charlton, S.
J.; Cuenoud, B.; Ernst, R.; Fairhurst, R. A.; Faller, B.; Farr, D.; Keller, T.; Fozard, J.;
Fullerton, J.; Garman, S.; Hatto, J.; Hayden, C.; He, H.; Howes, C.; Janus, D.; Jiang,
Z.; Lewis, C.; Loeuillet-Ritzler, F.; Moser, H.; Reilly, J.; Alan Steward, A.; Sykes,
D.; Tedaldi, L.; Trifilieff, A.; Tweed, M.; Watson, S.; Wissler, E.; Wyss, D. J. Med.
Chem. 2010, 53, 3675; (b) Alikhani, V.; Beer, D.; Bentley, D.; Bruce, I.; Cuenoud,
B. M.; Fairhurst, R. A.; Gedeck, P.; Haberthuer, S.; Hayden, C.; Janus, D.; Jordan,
L.; Lewis, C.; Smithies, K.; Wissler, E. Bioorg. Med. Chem. Lett. 2004, 14, 4705.
11. Nials, A. T.; Sumner, M. J.; Johnson, M.; Coleman, R. A. Br. J. Pharmacol. 1993,
108, 507.
the analogue 19 which exhibited a Clint of 291
ll/min/mg; the
a-substituted cyclopentylamines, as represented by the analogue
29 which exhibited a Clint value 781 ll/min/mg; and the monoter-
pene analogues, as represented by 33 which exhibited a Clint value
12. (a) Austin, R. P.; Barton, P.; Davis, A. M.; Fessey, R. E.; Wenlock, M. C. Pharm. Res.
2005, 22, 1649; (b) Austin, R. P.; Barton, P.; Bonnert, R. V.; Brown, R. C.; Cage, P.
E.; Cheshire, D. R.; Davis, A. M.; Dougall, I. G.; Ince, F.; Pairaudeau, G.; Young, A.
J. Med. Chem. 2003, 46, 3210.
13. Anderson, G. P.; Lindén, A.; Rabe, K. F. Eur. Respir. J. 1994, 7, 569.
14. (a) Bennett, J. A.; Harrison, T. W.; Tattersfield, A. E. Eur. Respir. J. 1999, 13, 445;
(b) Taburet, A.-M.; Schmit, B. Clin. Pharmacokinet. 1994, 26, 396.
15. Rosenborg, J.; Larsson, P.; Tegnér, K.; Hallström, G. Drug Metab. Dispos. 1999, 27,
1104.
16. (a) Suzuki, H.; Shindo, K.; Ueno, A.; Miura, T.; Takei, M.; Sakakibara, M.;
Fukamachi, H.; Tanaka, J.; Higa, T. Bioorg. Med. Chem. Lett. 1999, 9, 1361; (b)
Suzuki, H.; Ueno, A.; Takei, M.; Sindo, K.; Miura, T.; Sakakibora, M.; Higa, T.;
Fukamachi, H. Br. J. Pharmacol. 1999, 128, 716.
17. (a) Bonnert, R. V.; Brown, R. C.; Chapman, D.; Cheshire, D. R.; Dixon, J.; Ince, F.;
Kinchin, E. C.; Lyons, A. J.; Davis, A. M.; Hallam, C.; Harper, S. T.; Unitt, J. F.;
Dougall, I. G.; Jackson, D. M.; McKechnie, K.; Young, A.; Simpson, W. T. J. Med.
Chem. 1998, 41, 4915; (b) Weinstock, J.; Gaitanopoulos, D. E.; Stringer, O. D.;
Franz, R. G.; Hieble, J. P.; Kinter, L. B.; Mann, W. A.; Flaim, K. E.; Gessner, G. J.
Med. Chem. 1987, 30, 1166.
18. (a) Waldeck, B. Chirality 1993, 5, 350; (b) Trofast, J.; Österberg, K.; Källström, B.-
L.; Waldeck, B. Chirality 1991, 3, 443; (c) Murase, K.; Mase, T.; Ida, H.;
Takahashi, K.; Murakami, M. Chem. Pharm. Bull. 1978, 26, 1123.
19. Fairhurst, R. A.; Janus, D.; Lawrence, A. Org. Lett. 2005, 7, 4697.
20. Tucker, C. E.; Majid, T. N.; Knochel, P. J. Am. Chem. Soc. 1992, 114, 3983.
21. Corey, E. J.; Bakshi, R. K.; Shibita, S. J. J. Am. Chem. Soc. 1987, 109, 5551.
22. Shuker, A. J.; Siegel, M. J.; Matthews, D. P.; Weigel, L. O. Tetrahedron Lett. 1997,
38, 6149.
589 l/min/mg. Therefore, these series of N-substituents were
l
identified as being of particular interest for further follow-up activ-
ities based upon the proposed hypothesis. In contrast, the ana-
logues bearing additional basic groups in the amino substituent
exhibited lower glucuronidation rates, for example, the tribasic
analogue 36 proved to be resistant to metabolism in the in vitro
rat microsome assay in the presence of the UDPGA cofactor.
In summary, as part of a project with the overall goal to identify
once-daily inhaled bronchodilators with improved profiles we
have explored a 4-hydroxybenzothiazolone series of b2-adrenocep-
tor agonists 1 based upon the marine natural product S1319. An
efficient synthetic route to the series 1, as single stereoisomers,
has been described which makes use of a benzyne-mediated cycli-
sation as the key transformation. This route supported a parallel
synthetic approach for the introduction of a diverse range of N-
substituents, within a defined lipophilicity window, of which a
high proportion was shown to be highly potent and efficacious
agonists of the human b2-adrenoceptor. An in vitro glucuronida-
tion screen further identified analogues with the potential for im-
proved side-effect profiles based upon the proposed hypothesis for
minimising the systemic impact of the agonists following inhaled
23. Available Chemical Directory (ACD) database originally by MDL Systems Inc.,
delivery. This approach identified the b-phenethyl,
a-substituted
24. Ki values were determined by the ability of the test compounds to displace 3H-
CGP12177 from membranes derived from insect Sf21 cells expressing either
the human b1- or b2-adrenoceptor. All the data in Table 1 from the screening of
the library are means from duplicate determinations.
cyclopentyl and monoterpene amino-substituted analogues of 1
as particularly interesting for more extensive evaluation having
satisfied the hypothesised potency and clearance profiles. Further
studies exploring the potential of these lead 4-hydrox-
ybenzothiazolone series as once-daily bronchodilators will be the
subject of future publications.
25. pEC50 values were determined from the concentrations of cAMP measured
using
a-screen technology in cell lysates from A431 cells endogenously
expressing the b2-adrenoceptor following incubation with the test compounds.
26. pKa values were calculated using: Jelfs, S.; Ertl, P.; Selzer, P. J. Chem. Inf. Model.
2007, 47, 450. log P values were calculated using; c log P version 7.4, BioByte
Corporation.
27. Functional b1-adenoceptor activity of the test compounds was assessed using
electrically stimulated guinea-pig left-atria preparations as described in:
Battram, C.; Charlton, S. J.; Cuenoud, B.; Dowling, M. R.; Fairhurst, R. A.; Farr,
D.; Fozard, J. R.; Leighton-Davies, J. R.; Lewis, C. A.; McEvoy, L.; Turner, R. J.;
Trifilieff, A. J. Pharmacol. Exp. 2006, 371, 762.
28. (a) Deyrup, M. D.; Nowicki, S. T.; Richards, N. G. J.; Otero, D. H.; Harrison, J. K.;
Baker, S. P. Naunyn-Schmiedebergs Arch. Pharmacol. 1999, 359, 168; (b) Kaiser,
C. Drugs Affecting the Respiratory System. ACS Symposium Series 1980; Vol. 118,
Chapter 13.
29. Biel, J. H.; Schwarz, E. G.; Sprengeler, E. P.; Leiser, H. A.; Friedman, H. L. J. Am.
Chem. Soc. 1954, 76, 3149.
References and notes
1. (a) Hanania, N. A. Pulm. Pharmacol. Ther. 2008, 21, 540; (b) Sin, D. D.; Man, S. F.
P. Curr. Opin. Pulm. Med. 2007, 13, 90; (c) Miller-Larsson, A.; Selroos, O. Curr.
Pharm. Des. 2006, 12, 3261; (d) Centanni, S.; Di Marco, F. Expert Opin.
Pharmacother. 2005, 6, 2525; (e) Johnson, M. Proc. Am. Thorac. Soc. 2004, 1, 200.
2. (a) Ying, Y.; Leung, K. M.; Berkbigler, D.; Halbert, R. J.; Legorreta, A. P. J. Eval.
Clin. Pract. 1999, 5, 213; (b) Bosley, C. M.; Parry, D. T.; Cochrane, G. M. Eur.
Respir. J. 1994, 7, 504.
3. (a) Giembycz, M. A.; Kaur, M.; Leigh, R.; Newton, R. Br. J. Pharmacol. 2008, 153,
1090; (b) Ankerst, J. J. Asthma 2005, 49, 715; (c) Chapman, K. R. Expert Opin.
Pharmacother. 2002, 3, 341.
4. (a) Bouyssou, T.; Hoenke, C.; Rudolf, K.; Lustenberger, S. P.; Sieger, P.; Lotz, R.;
Heine, C.; Büttner, F. H.; Schnapp, A.; Konetzki, I. Bioorg. Med. Chem. Lett. 2010,
20, 1410; (b) Hoenke, C.; Bouyssou, T.; Tauternann, C. S.; Rudolf, K.; Schnapp,
A.; Konetzki, I. Bioorg. Med. Chem. Lett. 2009, 19, 6640; (c) Bouyssou, T.; Rudolf,
K.; Hoenke, C.; Lustenberger, P.; Schnapp, A.; Konetzki, I. Bioorg. Med. Chem.
Lett. 2009, 19, 5237; (d) Procopiou, P. A.; Barrett, V. J.; Bevan, N. J.; Biggadike, K.;
Butchers, P. R.; Coe, D. M.; Conroy, R.; Edney, D. D.; Field, R. N.; Guntrip, S. B.;
Looker, B. E.; McLay, I. M.; Monteith, M. J.; Morrison, V. S.; Mutch, P. J.; Richards,
S. A.; Sasse, R.; Smith, C. E. J. Med. Chem. 2009, 52, 2280; (e) Brown, A. D.;
Bunnage, M. E.; Glossop, P. A.; James, K.; Jones, R.; Lane, C. A. L.; Lewthwaite, R.
A.; Mantell, S.; Perros-Huguet, C.; Price, D. A.; Trevethick, M.; Webster, R.
30. (a) Daniel, W. A. Nova Acta Leopoldina 2003, 87, 101; (b) Lüllmann, H.; Wehling,
M. Biochem. Pharmacol. 1979, 28, 3409.
31. The susceptibility of the test compounds to undergo glucuronidation was
assessed in vitro using pooled rat hepatic microsome preparations;
microsomes (protein concentration 1 mg/ml) were incubated with
alamethicin and the test compounds (1 lM) at 37 °C for 15 min prior to the
addition of the co-factor UDPGA. Aliquots were removed at 0, 5, 15 and 30 min.
Reactions were stopped by addition of acetonitrile and samples were
subsequently analysed by LC–MS/MS after protein precipitation. The data
were analysed as percentage disappearance of parent relative to the zero time
sample and are expressed as intrinsic clearance rates.