Arylcyclopropanecarboxyl Guanidines as Novel, Potent, and Selective Inhibitors of the Sodium Hydrogen Exchanger Isoform-1

Abstract

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.

Microbial hydroxylation of o-bromophenylacetic acid: synthesis of 4-substituted-2,3-dihydrobenzofurans

“…The separated organic layer was combined, dried (MgSO 4 ), and evaporated to obtain 93 mg of clean phenol 12. 1 …”

“…The solvent was removed under reduced pressure and the residue was chromatographed (6% EtOAc:hexanes) to give a colorless oil, which crystallized on standing to provide 17.9 mg of 14 (90%). 1 …”

“…In these programs, several interesting syntheses of dihydrobenzofurans have been reported. During our melatonin receptor agonist [7,8,21,24] and sodium hydrogen exchange (NHE) programs [1,2], we needed to develop 2,3-dihydrobenzofuran as a core structure which would allow facile access to 4-substituted-2,3-dihydrobenzofurans. We envisioned accomplishing this by microbial hydroxylation [14] of 2-bromophenylacetic acid (7), thus providing a suitable substrate (9).…”

Inhibitors of sodium-hydrogen exchange as therapeutic agents for the treatment of heart disease

“…As summarised in Table 1, a long list of NHE-1-specific inhibitors have been developed by various pharmaceutical houses targeted primarily at cardiovascular therapeutics, the most recent being zoniporide (Pfizer) [46] and sabiporide (Boehringer-Ingelheim) [47]. BMS-284640, an arylcyclopropanecarboxyl guanidine recently synthesised by Bristol-Myers Squibb, has been shown to be a potent NHE-1-selective inhibitor with ∼ 380 times higher potency than cariporide [48]. Although these drugs have distinct characteristics, they all share a common ability to selectively inhibit NHE-1, rendering them particularly attractive for therapeutic interventions for cardiac disorders while minimising the potential for side effects.…”

3-Substituted-(5-arylfuran-2-ylcarbonyl)guanidines as NHE-1 inhibitors

“…Earlier reports suggest that functionality adjacent to the acylguanidine moiety leads to improved NHE-1 inhibitory potency, presumably due to an increase in hydrophobic interactions and/or reduction in the conformational flexibility of the acylguanidine group. [4][5][6] Herein, we summarize the results of studies evaluating NHE-1 inhibition by (5-arylfuran-2-ylcarbonyl)guanidines that contain amine, alkyl and aryl groups at the 3-position of the furan ring.…”