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Ahmad, S. et al.

Ahmad, Doweyko, Dugar, Grazier, Ngu, Wu, Yost, Chen, Gougoutas, DiMarco, Lan, Gavin, Chen, Dorso, Serafino, Kirby, Atwal,

Arylcyclopropanecarboxyl guanidines as novel, potent, and selective inhibitors of the sodium hydrogen exchanger isoform-1.

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 (IC(50) = 3.5 microM) shows inhibitory activity comparable to cariporide (IC(50) = 3.4 microM). 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, IC(50) = 0.003 microM). 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.[1]

References

Arylcyclopropanecarboxyl guanidines as novel, potent, and selective inhibitors of the sodium hydrogen exchanger isoform-1. 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. J. Med. Chem. (2001) [Pubmed]

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