Novel 2-imidazoles as potent and selective α1A adrenoceptor partial agonists

Bioorganic and Medicinal Chemistry Letters

Volumn 18, Issue 9, 2008, Pages 2930-2934

  Whitlock, Gavin A ^a   Conlon, Kelly ^a   McMurray, Gordon ^a   Roberts, Lee R ^a   Stobie, Alan ^a   Thurlow, Richard J ^a  

^a PFIZER GLOBAL RESEARCH AND DEVELOPMENT   (United Kingdom)

Author keywords

1A Adrenoceptor; 2 Imidazole; Drug like properties; Partial agonist; Selectivity

Indexed keywords

ALPHA 1A ADRENERGIC RECEPTOR; ALPHA 1B ADRENERGIC RECEPTOR; ALPHA 1D ADRENERGIC RECEPTOR; ALPHA 2A ADRENERGIC RECEPTOR; ALPHA ADRENERGIC RECEPTOR STIMULATING AGENT; IMIDAZOLE DERIVATIVE; LIGAND; PARTIAL AGONIST; PYRAZOLE DERIVATIVE; SULFONAMIDE;

ARTICLE; CELL STRAIN CACO 2; CONTROLLED STUDY; DRUG IDENTIFICATION; DRUG POTENCY; DRUG SELECTIVITY; DRUG SYNTHESIS; HUMAN; HUMAN CELL; PHYSICAL CHEMISTRY; STRUCTURE ACTIVITY RELATION;

ADRENERGIC ALPHA-AGONISTS; HUMANS; IMIDAZOLES; MODELS, CHEMICAL; RECEPTORS, ADRENERGIC, ALPHA-1; RECEPTORS, ADRENERGIC, ALPHA-2; STRUCTURE-ACTIVITY RELATIONSHIP; SULFONAMIDES; URINARY INCONTINENCE;

EID: 42949169074     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2008.03.070     Document Type: Article

References (26)

1. Hieble J.P., Bylund D.B., Clarke D.E., Eikenburg D.C., Langer S.Z., Lefzowitz R.J., Minneman K.P., and Ruffolo Jr. R.R. Pharmacol. Rev. 47 (1995) 267
2. Zhong H., and Minneman K.P. Eur. J. Pharmacol. 375 (1999) 261
3. Taniguchi N., Hamada K., Ogasawara K., Ukai Y., Yoshikuni Y., and Kimura K. Eur. J. Pharmacol. 318 (1996) 117
4. Brune M.E., O'Neill A.B., Gauvin D.M., Katwala S.P., Altenbach R.J., Brioni J.D., Hancock A.A., and Sullivan J.P. J. Urol. 166 (2001) 1555
5. Carroll W.A., Altenbach R.J., Buckner S.A., Brioni J.D., Brune M.E., Kolasa T., Meyer M.D., and Sullivan J.P. Med. Chem. Res. 13 (2004) 134
6. Sorbera L.A., and Castaner J. Drugs Future 29 (2004) 216
7. Blue D.R., Daniels D.V., Gever J.R., Jett M.F., O'Yang C., Tang H.M., Williams T.J., and Ford A.P.D.W. BJU International 93 (2004) 162
8. Knepper S.M., Buckner S.A., Brune M.E., DeBernadis J.F., Meyer M.D., and Hancock A.A. J. Pharmacol. Exp. Ther. 274 (1995) 97
9. Meyer M.D., Altenbach R.J., Hancock A.A., Buckner S.A., Knepper S.M., and Kerwin Jr. J.F. J. Med. Chem. 39 (1996) 4116
10. Altenbach R.J., Khilevich A., Meyer M.D., Buckner S.A., Milicic I., Daza A.V., Brune M.E., O'Neill A.B., Gauvin D.M., Cain J.C., Nakane M., Holladay M.W., Williams M., Brioni J.D., and Sullivan J.P. J. Med. Chem. 45 (2002) 4395
11. Buckner S.A., Milicic I., Daza A.V., Meyer M.D., Altenbach R.J., Williams M., Sullivan J.P., and Brioni J.D. Eur. J. Pharmacol. 449 (2002) 159
12. Odink, D. A.; Sue, I.-L.; Visor, G. C. WO Patent 02/38133, 2002.
13. Rodrigues A.D., and Roberts E.M. Drug Metab. Dispos. 25 (1997) 651
14. Testa B., and Jenner P. Drug Metab. Rev. 12 (1981) 1
15. 1-receptor agonists, no 2-imidazoles were described. Bishop M.J. Curr. Topics Med. Chem. 7 (2007) 135
16. For an example where 2-substitution of an imidazole reduced P450 inhibitory activity, see. Tang C., Chiba M., Nishime J., Hochman J.H., Chen I., Williams T.M., and Lin J.H. Drug Metab. Dispos. 28 (2000) 680
17. Amemiya Y., Venkataraman B.V., Patil P.N., Shams G., and Romstedt K. Egypt. J. Pharm. Sci. 35 (1994) 403
18. Amemiya Y., Hong S.S., Venkataraman B.V., Patil P.N., Shams G., Romstedt K., Feller D.R., Hsu F.L., and Miller D.D. J. Med. Chem. 35 (1992) 750
19. Imidazole final compounds were screened as racemic mixtures apart from example 17, which was separated into single enantiomers by chiral preparative HPLC.
20. max calculated as a percent relative to 10 μM phenylephrine response.
21. max calculated as a percent relative to 1 μM dexmeditomidine response.
22. Analogue 17 was separated by chiral HPLC into enantiomers 17a and 17b, although absolute stereochemistry was not determined at this time.
23. 1A agonist activity have been reported,. Bishop M.J., Barvian K.A., Berman J., Bigham E.C., Garrison D.T., Gobel M.J., Hodson S.J., Irving P.E., Liacos J.A., Navas III F., Saussy Jr. D.L., and Speake J.D. Bioorg. Med. Chem. Lett. 12 (2002) 471
24. Navas III F., Bishop M.J., Garrison D.T., Hodson S.J., Speake J.D., Bigham E.C., Drewry D.H., Saussy D.L., Liacos J.A., Irving P.E., and Gobel M.J. Bioorg. Med. Chem. Lett. 12 (2002) 575
25. Hodson S.J., Bigham E.C., Garrison D.T., Gobel M.J., Irving P.E., Liacos J.A., Navas III F., Saussy Jr. D.L., Sherman B.W., Speake J.D., and Bishop M.J. Bioorg. Med. Chem. Lett. 12 (2002) 3449
26. Speake J.D., Navas III F., Bishop M.J., Garrison D.T., Bigham E.C., Hodson S.J., Saussy D.L., Liacos J.A., Irving P.E., and Sherman B.W. Bioorg. Med. Chem. Lett. 13 (2003) 1183