KCO912: a potent and selective opener of ATP-dependent potassium (K ATP ) channels which suppresses airways hyperreactivity at doses devoid of cardiovascular effects

Abstract

ATP-sensitive potassium (K(ATP)) channel openers can obviate experimental airways hyperreactivity (AHR) and have shown therapeutic benefit in asthma. However, the clinical potential of such compounds has been compromised by cardiovascular side-effects. We report here the pharmacological properties of (3 S,4 R)-3,4-dihydro-3-hydroxy-2,2-dimethyl-4-(2-oxo-1-piperidinyl)- N-phenyl-2 H-1-benzopyran-6-sulphonamide (KCO912), a K(ATP) channel opener which suppresses AHR at doses devoid of cardiovascular effects.Specific interaction of KCO912 with the native vascular channel and the sulphonylurea receptor subunit (SUR2B) of the vascular K(ATP) channel was shown in radioligand binding assays. In rat aortic strips, KCO912 inhibited specific binding of [3H]P1075 and [3H]glibenclamide with up to 100% efficacy and with p Ki values of 8.28 and 7.96, respectively. In HEK cells transfected with the recombinant vascular K(ATP) channel (Kir6.1 + SUR2B), the compound elicited a concentration-dependent outward current (pEC50 6.8) and in preloaded rat aortic rings it induced a concentration-dependent glibenclamide-sensitive 86Rb+ efflux (pEC50 7.51). Following intratracheal (i.t.) administration of KCO912 to guinea pigs, AHR induced by immune complexes or ozone was rapidly (<5 min) reversed (ED50 values 1 microg/kg and 0.03 microg/kg, respectively). Changes in blood pressure were seen only at doses =100 microg/kg yielding 'therapeutic ratios' of 100 and 3333, respectively. In addition, KCO912 reversed AHR induced by lipopolysaccharide (LPS; ED50 0.5 microg/kg i.t.) and a dose of 1 microg/kg i.t. fully reversed AHR induced by subchronic treatment with salbutamol. At doses which suppressed AHR, KCO912 had no anti-bronchoconstrictor effects in normoreactive guinea pigs. In spontaneously hyperreactive rhesus monkeys, KCO912, given by inhalation, inhibited methacholine-induced bronchoconstriction (ED50 1.2 microg/kg) but had no significant effects on blood pressure or heart rate at all doses tested (therapeutic ratio >100). In rats given 3 mg/kg of KCO912 by inhalation, the ratio of the area under the concentration-time curve (AUC) for lung to the AUC in blood was 190 and the compound was rapidly cleared (initial t1/2 approximately 30 min). Thus, the wide therapeutic window following administration of KCO912 to the lung seems likely to reflect slow or incomplete passage of KCO912 from the lung into the systemic circulation coupled with rapid removal from the systemic circulation.Thus, when given locally to the airways in both guinea pigs and monkeys, KCO912 suppresses AHR at doses devoid of cardiovascular effects and has a significantly better therapeutic window than representative earlier generation K(ATP) channel openers defined in the same models. Given the pivotal role of AHR in the pathophysiology of asthma and the preclinical profile of KCO912, this compound was selected for clinical evaluation.

Structure-Activity Relationships of KATP Channel Openers

“…Chemical characterics of KCO912 26 are a 6-Nsulfonamido substituent and a 4-piperidone moiety [45]. Because compounds with this 6-substituent [32] lack airways selectivity, the 4-piperidone moiety (also present in BRL 55834) coupled with the chromanol structure might be responsible for this tissue-selective behaviour.…”

Beyond the dogma: novel 2-adrenoceptor signalling in the airways

“…However, although K ATP channel openers oppose bronchoconstriction, attenuate airways hyperreactivity and may play a role in b 2 -adrenocepotormediated relaxation of vascular smooth muscle, the effect of selective agonists, per se, on these channels in human ASM is not well studied [112][113][114]. Nevertheless, K ATP channels are phosphorylated and activated by PKA in response to cAMP analogues, forskolin and isoprenaline [115,116], and could, therefore, play a role in b 2 -adrenoceptor-mediated relaxation of ASM (fig.…”

Binding and effect of KATP channel openers in the absence of Mg2+

“…Major representatives of the KCOs are the cyanoguanidines such as pinacidil and N ‐cyano‐ N ′‐(1,1‐dimethylpropyl)‐ N ″‐3‐pridylguanidine (P1075), the benzopyrans such as levcromakalim, and rilmakalim and the thioformamides like aprikalim; in addition, there are special cases like minoxidil sulphate, nicorandil and diazoxide (see Figure 1 for structures). New openers are being developed as therapies for asthma and cardiac ischaemia (benzopyrans, Buchheit et al ., 2002; Grover et al ., 2002) and irritable bladder (dihydropyridines, Gopalakrishnan et al ., 2002).…”