title: Thiophene systems. 14. Synthesis and antihypertensive activity of novel 7-(cyclic amido)-6-hydroxythieno[3,2-b]pyrans and related compounds as new potassium channel activators.
abstract: The synthesis and antihypertensive activity of novel 7-(cyclic amido)-6-hydroxy-5,5-dimethylthieno[3,2-b]pyrans and related compounds are described. The compounds were tested for oral antihypertensive activity in spontaneously hypertensive rats (SHR) and selected compounds were evaluated in vitro for increases in 86Rb efflux in rabbit isolated mesenteric arteries. The effects on activity in SHR of lactam ring size, the presence of heteroatoms in the lactam ring, the relative stereochemistry at C-6 and C-7, and the substituents on the thiophene ring are examined. The best racemic compound in this series is 32, trans-5,6-dihydro-6-hydroxy-5,5-dimethyl-2-nitro-7-(2-oxopiperidin -1-yl)-5H- thieno[3,2-b]pyran, which is 10-fold more potent than cromakalim with an ED30 = 0.015 mg/kg in SHR. Compound 32 could be resolved and the antihypertensive activity determined to reside primarily in the (6S,7S)-(-)-enantiomer 41. Surprisingly, the elimination of water to give the enamides 50-52, thiophene isosteres of bimakalim, diminishes activity significantly.
authors.affiliation: R.W. Johnson Pharmaceutical Research Institute, Spring House, Pennsylvania 19477-0776.
authors.forename: P J
authors.initials: PJ
authors.lastname: Sanfilippo
authors.forename: J J
authors.initials: JJ
authors.lastname: McNally
authors.forename: J B
authors.initials: JB
authors.lastname: Press
authors.forename: L J
authors.initials: LJ
authors.lastname: Fitzpatrick
authors.forename: M J
authors.initials: MJ
authors.lastname: Urbanski
authors.forename: L B
authors.initials: LB
authors.lastname: Katz
authors.forename: E
authors.initials: E
authors.lastname: Giardino
authors.forename: R
authors.initials: R
authors.lastname: Falotico
authors.forename: J
authors.initials: J
authors.lastname: Salata
authors.forename: J B
authors.initials: JB
authors.lastname: Moore
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D015221:Potassium Channels / Q000187:drug effects*; D011714:Pyrans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D011918:Rats, Inbred SHR; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000959:Antihypertensive Agents; D015221:Potassium Channels; D011714:Pyrans; D013876:Thiophenes; C078276:RWJ 26629