title: Novel cAMP PDE III inhibitors: 1,6-naphthyridin-2(1H)-ones.
abstract: Two series of medorinone (3) analogs were prepared by modifications at C(2) and C(5). The C(2)-series was prepared from 2-chloro-5-methyl-1,6-naphthyridine (4) by replacement of the chloro group with various nucleophiles. The C(5)-series was prepared from 5-acyl-6-[2-(dimethylamino)-ethenyl]-2(1H)-pyridinone (11), 5-bromo-1,6-naphthyridin-2(1H)-one (17), and 1,3-diketones 19 and 27. 1,6-Naphthyridin-2(1H)-ones are novel inhibitors of cAMP PDE III. Modification of the carbonyl group of 3 or N-methylation at N(1) resulted in a dramatic loss of enzyme activity. Absence of the C(5)-methyl group of medorinone (3) or its shift to C(3) or C(7) also resulted in reduced activity. Substitution at C(3) also diminished activity. However, substitution at C(5) by a wide variety of substituents led to improvement of enzyme activity and several C(5)-substituted analogs were more potent than milrinone.
authors.affiliation: Sterling Winthrop Pharmaceuticals Research Division, Rensselaer, New York 12144.
authors.forename: B
authors.initials: B
authors.lastname: Singh
authors.forename: G Y
authors.initials: GY
authors.lastname: Lesher
authors.forename: K C
authors.initials: KC
authors.lastname: Pluncket
authors.forename: E D
authors.initials: ED
authors.lastname: Pagani
authors.forename: D C
authors.initials: DC
authors.lastname: Bode
authors.forename: R G
authors.initials: RG
authors.lastname: Bentley
authors.forename: M J
authors.initials: MJ
authors.lastname: Connell
authors.forename: L T
authors.initials: LT
authors.lastname: Hamel
authors.forename: P J
authors.initials: PJ
authors.lastname: Silver
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000818:Animals; D002316:Cardiotonic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004285:Dogs; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009287:Naphthyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D002316:Cardiotonic Agents; D004791:Enzyme Inhibitors; D009287:Naphthyridines; D015105:3',5'-Cyclic-AMP Phosphodiesterases