title: Structure-activity studies for a novel series of tricyclic dihydropyridopyrazolones and dihydropyridoisoxazolones as K(ATP) channel openers.
abstract: In search of a novel chemotype of K(ATP) channel openers a series of tricyclic dihydropyridopyrazolones and dihydropyridoisoxazolones was synthesized. It was found that cyclopentanone in the left hand portion of the molecule was 4-fold more potent than cyclohexanone. Introduction of gem-dimethyl groups as well as incorporation of oxygen in the cyclohexanone ring in the left hand portion of the molecule increased the potency 10-fold. In the right hand portion of the molecule, the NH-group of the pyrazolone can be effectively substituted by oxygen increasing the activity 5-fold. Incorporation of a methyl group adjacent to the dihydropyridine (DHP) nitrogen not only significantly boosted activity, but also provided an additional benefit of increased metabolic stability. In vitro tests on the tissue from pig bladder strips provided further confirmation of K(ATP) activity of these compounds.
authors.affiliation: Neuroscience Research, GPRD, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064-6101, USA. irene.drizin@abbott.com
authors.forename: Irene
authors.initials: I
authors.lastname: Drizin
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Altenbach
authors.forename: Steven A
authors.initials: SA
authors.lastname: Buckner
authors.forename: Kristi L
authors.initials: KL
authors.lastname: Whiteaker
authors.forename: Victoria E
authors.initials: VE
authors.lastname: Scott
authors.forename: John F
authors.initials: JF
authors.lastname: Darbyshire
authors.forename: Venkata
authors.initials: V
authors.lastname: Jayanti
authors.forename: Rodger F
authors.initials: RF
authors.lastname: Henry
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Coghlan
authors.forename: Murali
authors.initials: M
authors.lastname: Gopalakrishnan
authors.forename: William A
authors.initials: WA
authors.lastname: Carroll
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D008565:Membrane Proteins / Q000819:agonists / Q000502:physiology*; D010081:Oxazolone / Q000737:chemistry* / Q000494:pharmacology; D015221:Potassium Channels / Q000819:agonists / Q000502:physiology*; D011720:Pyrazoles / Q000737:chemistry* / Q000494:pharmacology; D047069:Pyrazolones; D011725:Pyridines / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013552:Swine
chemical_list: D008565:Membrane Proteins; D015221:Potassium Channels; D011720:Pyrazoles; D047069:Pyrazolones; D011725:Pyridines; C117780:mitochondrial K(ATP) channel; D010081:Oxazolone; C038362:pyrazolone; C023666:pyridine