| Autor: |
Ahmad, S., Doweyko, L. M., Dugar, S., Grazier, N., Ngu, K., Wu, S. C., Yost, K. J., Chen, B.-C., Gougoutas, J. Z., DiMarco, J. D., Lan, S.-J., Gavin, B. J., Chen, A. Y., Dorso, C. R., Serafino, R., Kirby, M., Atwal, K. S. |
| Zdroj: |
Journal of Medicinal Chemistry; September 2001, Vol. 44 Issue: 20 p3302-3310, 9p |
| Abstrakt: |
A novel series of arylcyclopropanecarboxyl guanidines was synthesized and evaluated for activity against the sodium hydrogen exchanger isoform-1 (NHE-1). In biological assays conducted in an AP1 cell line expressing the human NHE-1 isoform, the starting cyclopropane 3a (IC50 = 3.5 μM) shows inhibitory activity comparable to cariporide (IC50 = 3.4 μM). Structure−activity relationships are used to optimize the affinity of various acyl guanidines for NHE-1 by screening the effect of substituents at both aryl and cyclopropyl rings. It is demonstrated that introduction of appropriate hydrophobic groups at the phenyl ring and a gem-dimethyl group at the cyclopropane ring enhances the NHE-1 inhibitory activity by up to 3 orders of magnitude (compound 7f, IC50 = 0.003 μM). In addition, the gem-dimethyl series of analogues seem to display improved oral bioavailability and longer plasma half-life in rats. Furthermore, the lead benzodihydrofuranyl analogue 1 (BMS-284640) shows over 380-fold increased NHE-1 inhibitory activity as well as improved selectivity for NHE-1 over NHE-2 compared to cariporide. |
| Databáze: |
Supplemental Index |
| Externí odkaz: |
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