title: 6-Sulfonylchromenes as highly potent K(ATP)-channel openers.
abstract: We synthesized K(ATP)-channel openers (KCOs) composed of the 4-pyridonechromene moiety of bimakalim (1) and a variety of sulfonyl-containing 6-substituents 4-29. Dilator potencies were measured in rat aorta and trachea. In both test systems the KCOs exhibit potency ranges of roughly 3 log units. The 6-N-phenyl-N-methylsulfonamido derivative 24 shows the highest potency. In rat aorta the potency spectrum ranges from a pEC(50) value of 8.76 to 5.68; in rat trachea it ranges from 8.01 to 4.99. On average, the dilator activity is about 0.8 log units stronger in the aorta. Aortic relaxation by chromene 13 is markedly retarded, the clinical relevance of which (e.g., preventing tachycardia) remains to be clarified. Binding affinities were determined in myocardial membranes and aortic smooth muscle cells of the rat. The affinity spectrum in myocardial membranes ranges from a pK(D) of 7.83 to 5.18; the highest affinity in aortic smooth muscle cells is measured for compound 28 (pK(D) = 8.55), whereas the lowest affinity is measured for 4 (pK(D) = 4.51). Significant selectivities discriminating between K(ATP)-channels of different organs could not be detected. PLS analysis yielded no significant correlation between vasodilator activity in aorta and chemical descriptors (GRIND). Compounds 13, 24, and 28 represent the most potent KCOs of the 4-pyridonechromene type published so far. Their 6-substituents exhibit a phenyl ring with a congruent conformational orientation in relation to the sulfonylchromene. From SAR data and conformational analysis we postulate that these new 6-substituents extend the binding site for chromene KCOs. Correspondingly, we assume that the receptor area exhibits two separate interaction sites with the capacity to bind 6-substituents: (a) one site interacting with negatively polarized partial structures (e.g., CN, NO(2), SO(2)) and (b) one spatially restricted site enabling favorable pi-interactions.
authors.affiliation: Institute of Pharmaceutical Chemistry, Heinrich-Heine-Universität, Universitätsstrasse 1, D-40225 Düsseldorf, Germany.
authors.forename: Ekkehart
authors.initials: E
authors.lastname: Salamon
authors.forename: Raimund
authors.initials: R
authors.lastname: Mannhold
authors.forename: Horst
authors.initials: H
authors.lastname: Weber
authors.forename: Horst
authors.initials: H
authors.lastname: Lemoine
authors.forename: Walter
authors.initials: W
authors.lastname: Frank
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D001011:Aorta / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D001578:Benzopyrans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D066298:In Vitro Techniques; D015640:Ion Channel Gating; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D009126:Muscle Relaxation; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D015221:Potassium Channels / Q000187:drug effects*; D011485:Protein Binding; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D001578:Benzopyrans; D015221:Potassium Channels; D013450:Sulfones; D000255:Adenosine Triphosphate