Cardioselective Anti-Ischemic ATP-Sensitive Potassium Channel Openers. 3. Structure-Activity Studies on Benzopyranyl Cyanoguanidines; Modification of the Cyanoguanidine Portion

Abstract

Structure-activity relationships for the cyanoguanidine portion of the lead cardiac selective ATP-sensitive potassium channel (KATP) opener (3) are described. The cyanoguanidine moity appears to be optimal since increasing or decreasing the distance between the aniline nitrogen and the pendant aromatic ring attenuates anti-ischemic potency/selectivity. Similarly, unfavorable results are obtained by replacement of the aniline nitrogen with other linkers (CH2, S, O). Replacement of the phenyl ring with a methyl group diminishes cardiac selectivity. Constraining the urea moiety into a benzimidazolone or imidazolone ring retains anti-ischemic potency with significant improvement in cardiac selectivity. As shown by the ratio of vasorelaxant and anti-ischemic potencies, the cardiac selectivity in vitro varies over 3 orders of magnitude. These data are in agreement with previous results indicating that distinct structure-activity relationships exist for the anti-ischemic and vasorelaxant activities. Since the anti-ischemic effects of this series of compounds are abolished by pretreatment with structurally different KATP blockers (glyburide, sodium 5-hydroxydecanoate, meclofenamic acid), the mechanism for the anti-ischemic actions of these compounds still appears to involve the opening of KATP.

4‐[18F]fluorophenyl ureas via carbamate‐4‐nitrophenyl esters and 4‐[18F]fluoroaniline

“…Reactions of amines with 4-nitrophenyl chloroformate lead to carbamate 4-nitrophenylesters. 3,22 These substances are stable under standard conditions and easy to separate. Further reaction with another amine gives disparately substituted ureas.…”

“…with halogen) are found quite often. 3,4 Until now, there is no example where these structures are used for the preparation of no-carrier-added (n.c.a.) fluorine-18 labelled analogue or original tracers for diagnostics with positron-emission-tomography (PET).…”

Second-Generation KATP Channel Openers

“…(3)) was the first cardioselective KCO [42]. Starting from BMS-180448 Atwal et al [43][44][45][46][47] performed detailed SAR studies (Fig. 4).…”

“…Modifications of the cyanoguanidine portion [44] show that a phenyl cyanoguanidine or phenyl urea moiety strongly favor cardioselectivity; modifying the distance between aniline nitrogen and the pendant aromatic ring attenuates potency and selectivity. Replacements of the aniline N by O, S, or CH 2 are detrimental as well.…”

Novel Conversion of 4-Aminoquinolines to New Tricyclic (<i>R,S</i>)-3-Methylazeto[3,2-<i>c</i>] Quinolin-2(2a<i>H</i>)-Ones and Versatile One Step Synthesis of <i>N</i>-(Quinolin-4-yl) Carbamates from 4-Aminoquinolines

“…Similarly, interacting the intermediate 4-nitrophenyl carbonate ester with the adjacent amino function (4) leads to the formation of oxazolidin-2-one derivatives (5). [2][3][4][5] Using the same approach, Izdebski et al 6 reported a convenient method for the preparation of symmetrical and unsymmetrical 1,3-disubstituted ureas (9) by treating amines (6) with 1 to give 4-nitrophenyl N-alkylcarbamates (7), followed by reacting the mixture with the second amines (8). This strategy was later utilized to prepare biologically active compounds including: 1) pyridyl urea analogues as cardioselective anti-ischemic ATP-sensitive potassium channel openers; 2) N-(ureidoalkyl)-benzyl-piperidines as potent CC chemokine receptor-3 (CCR-3) antagonists;…”