title: Flavones. 2. Synthesis and structure-activity relationship of flavodilol and its analogues, a novel class of antihypertensive agents with catecholamine depleting properties.
abstract: (3-Phenyl-7-flavonoxy)propanolamines have been shown to exhibit antihypertensive activity in spontaneously hypertensive rats. Although they are structurally similar to classical beta-adrenergic blocking compounds, their activity is not due to inhibition of beta-adrenoceptors. In the present study, a series of simple flavonoxypropanolamines was prepared to further explore the structural requirements for the antihypertensive effect of these compounds. A structure-activity relationship of these derivatives indicates that the position of the oxypropanolamine side chain, the hydroxy group of the side chain, steric bulkiness and length of N substituents, degree of the N-substitution, phenyl group at the 2-position of the chromone nucleus, and substituents of the phenyl group or B ring of the flavone play significant roles in imparting pharmacological effects. In addition, there is a good correlation between the antihypertensive activity and depletion of myocardial norepinephrine. Of these analogues tested, the most effective one was flavodilol. Only the 8-substituted analogue 6 was found to be a beta-antagonist. Flavodilol was chosen for in-depth pharmacological, toxicological, and clinical evaluation.
authors.affiliation: Department of Organic Chemistry, Pennwalt Corporation, Rochester, New York 14623.
authors.forename: E S
authors.initials: ES
authors.lastname: Wu
authors.forename: T E
authors.initials: TE
authors.lastname: Cole
authors.forename: T A
authors.initials: TA
authors.lastname: Davidson
authors.forename: M A
authors.initials: MA
authors.lastname: Dailey
authors.forename: K G
authors.initials: KG
authors.lastname: Doring
authors.forename: M
authors.initials: M
authors.lastname: Fedorchuk
authors.forename: J T
authors.initials: JT
authors.lastname: Loch
authors.forename: T L
authors.initials: TL
authors.lastname: Thomas
authors.forename: J C
authors.initials: JC
authors.lastname: Blosser
authors.forename: A R
authors.initials: AR
authors.lastname: Borrelli
mesh_terms: D000311:Adrenal Glands / Q000378:metabolism; D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis*; D001923:Brain Chemistry / Q000187:drug effects; D002395:Catecholamines / Q000378:metabolism; D055598:Chemical Phenomena; D002621:Chemistry; D002851:Chromatography, High Pressure Liquid; D005419:Flavonoids / Q000138:chemical synthesis* / Q000494:pharmacology; D006321:Heart / Q000187:drug effects; D008297:Male; D009206:Myocardium / Q000378:metabolism; D011412:Propanolamines / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D013329:Structure-Activity Relationship
chemical_list: D000959:Antihypertensive Agents; D002395:Catecholamines; D005419:Flavonoids; D011412:Propanolamines; C058114:flavodilol