title: Synthesis and biological activity of trans(+-)-N-methyl-2-(3-pyridyl)-2-tetrahydrothiopyrancarbothioamide 1-oxide (RP 49356) and analogues: a new class of potassium channel opener.
abstract: The synthesis and biological activity of trans-(+-)-N-methyl-2-(3-pyridyl)-2-tetrahydrothiopyrancarbothioamid+ ++ e 1-oxide (8a, RP 49356) and analogues is reported. These compounds constitute a new structural class of K(+)-channel opener. The effects of changes in pyridyl group, thioamide, and thiane ring on in vitro K(+)-channel opening reactivity are discussed. A 3-pyridyl or 3-quinolyl group, a small N-alkyl thioamide function, and a thiane oxide ring, in which the sulfoxide is in a trans relationship to the thioamide, are preferred for activity. Selected compounds were tested intravenously in the normotensive anaesthetized rat for hypotensive effects, and the activities reflect their in vitro K(+)-channel opening activity. This led to further evaluation of compound 8a and the selection of the (-)-enantiomer 8b (RP 52891) for development as an antihypertensive and antianginal agent.
authors.affiliation: Rhône-Poulenc Rorer, Dagenham Research Centre, Essex, England.
authors.forename: T J
authors.initials: TJ
authors.lastname: Brown
authors.forename: R F
authors.initials: RF
authors.lastname: Chapman
authors.forename: D C
authors.initials: DC
authors.lastname: Cook
authors.forename: T W
authors.initials: TW
authors.lastname: Hart
authors.forename: I M
authors.initials: IM
authors.lastname: McLay
authors.forename: R
authors.initials: R
authors.lastname: Jordan
authors.forename: J S
authors.initials: JS
authors.lastname: Mason
authors.forename: M N
authors.initials: MN
authors.lastname: Palfreyman
authors.forename: R J
authors.initials: RJ
authors.lastname: Walsh
authors.forename: M T
authors.initials: MT
authors.lastname: Withnall
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D004285:Dogs; D008297:Male; D008968:Molecular Conformation; D010847:Picolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects*; D011714:Pyrans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000959:Antihypertensive Agents; D010847:Picolines; D015221:Potassium Channels; D011714:Pyrans; C061043:aprikalim