Identification of metabolites of the tryptase inhibitor CRA-9249: Observation of a metabolite derived from an unexpected hydroxylation pathway

Bioorganic and Medicinal Chemistry Letters

Volumn 16, Issue 15, 2006, Pages 4053-4058

  Yu, Walter ^a   Dener, Jeffrey M ^a   Dickman, Daniel A ^a   Grothaus, Paul ^a   Ling, Yun ^a   Liu, Liang ^a   Havel, Chris ^a   Malesky, Kimberly ^a   Mahajan, Tania ^a   O'Brian, Colin ^a   Shelton, Emma J ^a   Sperandio, David ^a   Tong, Zhiwei ^a   Yee, Robert ^a   Mordenti, Joyce J ^a  

^a Celera Genomics ^*  (United States)

Author keywords

Active metabolite; Metabolism; Metabolite identification; Synthesis

Indexed keywords

AMIDE; BENZIMIDAZOLE DERIVATIVE; CRA 9249; DRUG METABOLITE; ETHER DERIVATIVE; TRYPTASE INHIBITOR;

ANIMAL TISSUE; ARTICLE; CHEMICAL STRUCTURE; CONTROLLED STUDY; DOG; DRUG IDENTIFICATION; DRUG METABOLISM; DRUG SYNTHESIS; HUMAN; HUMAN TISSUE; HYDROXYLATION; LIVER MICROSOME; METABOLITE; MONKEY; NONHUMAN; RABBIT; RAT;

ANIMALS; BENZIMIDAZOLES; CHROMATOGRAPHY, HIGH PRESSURE LIQUID; DOGS; ENZYME INHIBITORS; HYDROXYLATION; MACACA FASCICULARIS; MAGNETIC RESONANCE SPECTROSCOPY; RATS; SERINE ENDOPEPTIDASES; TRYPTASES;

CANIS FAMILIARIS; MACACA FASCICULARIS; ORYCTOLAGUS CUNICULUS;

EID: 33745232540     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2006.05.003     Document Type: Article

References (30)

1. Yan Z., and Caldwell G.W. Curr. Topics Med. Chem. 1 (2001) 403
2. Elkins S., Ring B.J., Grace J., McRobie-Belle D.J., and Wrighton S.A. J. Pharmacol. Toxicol. Methods 44 (2000) 313
3. Fura A., Shu Y.-Z., Zhu M., Hanson R.L., Roongta V., and Humphreys W.G. J. Med. Chem. 47 (2004) 4339
4. Rosenblum S.B., Huynh T., Alfonso A., Davis Jr. H.R., Yumibe N., Clader J.W., and Burnett D.A. J. Med. Chem. 41 (1998) 973
5. Clader J.W. J. Med. Chem. 47 (2001) 1
6. Piromohamed M., Kitteringham N.R., and Park B.K. Drug Safety 11 (1994) 114
7. Williams D.P., and Naisbitt D.J. Curr. Opin. Drug Disc. Dev. 5 (2002) 104
8. Nassar A.-E.F., DeMaio W., Davis M., and Talaat R.E. Curr. Drug Disc. (2004) 20
9. Janc J.W., Clark J.M., Warne R.L., Katz B.A., and Moore W.R. Biochemistry 39 (2000) 4792
10. Katz B.A., Clark J.M., Finer-Moore J.S., Jenkins T.E., Johnson C.R., Ross M.J., Luong C., Moore W.R., and Stroud R.M. Nature 391 (1998) 608
11. Church, T. J.; Cutshall, N. S.; Gangloff, A. R.; Jenkins, T. E.; Linsell, M. S.; Litvak, J.; Rice, K. D.; Spencer, J. R.; Wang, V. R. PCT Int. Appl. WO 9845275, 1998.
12. Dener, J. M.; O'Bryan, C.; Yee, R.; Shelton, E. J.; Sperandio, D.; Mahajan, T.; Palmer, J.; Spencer, J. R.; Tong. Z. Tetrahedron Letters, accepted for publication.
13. Finger G.C., Reed F.H., Burness D.M., Fort D.M., and Blough R.R. J. Am. Chem. Soc. 73 (1951) 145
14. Mittendorf, J.; Henning, R.; Raddatz, S.; Schlemmer, K.-H.; Hiraoka, M.; Kadono, H.; Mogi, M.; Moriwaki, T.; Murata, T.; Sakakibara, S.; Shimada,.M.; Yoshida, N.; Yoshino. T. PCT Int. Appl. WO 0020401, 2000. The sequence presumably goes through the monoamide and bis(amide) intermediates A and B. Yields of this process tended to be low due to the formation of symmetrical bis(amide) derivatives from two molecules of 14 with reaction 15.{A figure is presented}.
15. Sperandio D., Gangloff A.R., Litvak J., Goldsmith R., Hataye J.M., Wang V.R., Shelton E.J., Elrod K., Janc J.W., Clark J.M., Rice K., Weinheimer S., Yeung K.-S., Meanwell N.A., Hernandez D., Staab A.J., Venables B.L., and Spencer J.S. Bioorg. Med. Chem. Lett. 12 (2002) 3129
16. -.
17. For representative examples of metabolism-mediated N-dealkylation of amides in vitro and in vivo, please see the following references:. Sugnaux F.R., and Benakis A. Eur. J. Drug Metab. Pharmacokinet. 3 (1978) 235
18. Yoshida K., Manbu K., Arakawa S., Miyazaki H., and Hashimoto M. Biomed. Mass Spectrom. 6 (1979) 253
19. Schoenig G.P., Hartnagel Jr. R.E., Osimitz T.G., and Llanso S. Drug. Metab. Dispos. 24 (1996) 156
20. Constantino L., and Iley J. Xenobiotica 29 (1999) 409
21. Allen J.G., Blackburn M.J., and Caldwell S.M. Xenobiotica 1 (1971) 3-12
22. Ross D., Farmer P.B., Geschner A., Hickman J.A., and Threadgill M.D. Biochem. Pharmacol. 32 (1983) 1773
23. Tiller P.R., Land A.P., Jardine I., Murphy D.M., Sozio R., Ayrton A., and Schaefer W.H. J. Chromatogr. A 794 (1998) 15
24. Smith R.L., Bicking J.B., Gould N.P., Lee T.-J., Robb C.M., Keuhl Jr. F.A., Mandel L.R., and Cragoe Jr. E.J. J. Med. Chem 20 (1977) 540
25. The presence of imine 29 in this reaction was proposed based on LC-MS data from the crude product obtained from the synthesis of 23. Only a few reports of N-acylimines derived from aliphatic aldehydes are represented in the literature since these are known to isomerize to the corresponding enamide: Gizecki, P.; Dhal, R.; Poulard, C.; Gosselin, P.; Dujardin, G. J. Org. Chem. 2003, 68, 4338. Imine 29 may also be produced during the metabolism of 1 in liver microsomes, but it is expected to readily hydrolyze to 22 and 24 under the aqueous conditions employed (see also Ref. 19).
26. +.
27. 3).
28. The proton NMR spectrum of the metabolite changes upon storage for about one month. For example, the sharp doublet at 9.01 ppm disappears and two new signals are observed at 10.2 and 9.65 ppm. The latter signal is consistent with the chemical shift for the aldehyde proton in 28, as determined by the chemical shift for the aldehyde proton observed in the proton NMR spectrum from an authentic sample of the aldehyde.
29. i for this compound was determined to be 2.7 μM, about 100-fold less active than the synthetic sample of 23 and 3-fold less active than the parent compound 1.
30. Hydroxybenzimidazole 6 could have been a viable candidate for development due to its increased potency relative to 1; however, this option was not considered for two reasons. First of all, this class of inhibitors did not possess sufficient potency at pH 7.4 in physiological concentrations of free zinc. More importantly, we were unable to establish evidence for the formation of stable, inhibitory ternary complexes of zinc, tryptase, and 1 in the human mast cell granules (Amos Baruch and James Clark, unpublished work).