Molecular structure of the dihydropyridazinone cardiotonic 1,3-dihydro-3,3-dimethyl-5-(1,4,5,6-tetrahydro-6-oxo-3-pyridazinyl)-2H-indol-2-one, a potent inhibitor of cyclic AMP phosphodiesterase

The cardiotonic 1,3-dihydro-3,3-dimethyl-5-(1,4,5,6-tetrahydro-6-oxo-3- pyridazinyl)-2H-indol-2-one (1, LY195115) is a potent, competitive inhibitor (Ki = 80 nM) of sarcoplasmic reticulum derived phosphodiesterase (SR-PDE). Moreover, the compound is a potent positive inotrope both in vitro and in vi...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1987-04, Vol.30 (4), p.623-627
Main Authors: Robertson, David W, Jones, Noel D, Krushinski, Joseph H, Pollock, G. Don, Swartzendruber, John K, Hayes, J. Scott
Format: Article
Language:English
Subjects:
3',5'-Cyclic-AMP Phosphodiesterases - antagonists & inhibitors
Animals
Cardiotonic Agents - pharmacology
Cattle
Condensed matter: structure, mechanical and thermal properties
Dose-Response Relationship, Drug
Exact sciences and technology
Female
Heart - drug effects
Heterocyclic compounds
Indoles - pharmacology
Magnetic Resonance Spectroscopy
Male
Models, Molecular
Molecular Conformation
Organic compounds
Physics
Pyridazines - pharmacology
Sarcoplasmic Reticulum - enzymology
Structure of solids and liquids
crystallography
Structure of specific crystalline solids
Structure-Activity Relationship
X-Ray Diffraction
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Summary:The cardiotonic 1,3-dihydro-3,3-dimethyl-5-(1,4,5,6-tetrahydro-6-oxo-3- pyridazinyl)-2H-indol-2-one (1, LY195115) is a potent, competitive inhibitor (Ki = 80 nM) of sarcoplasmic reticulum derived phosphodiesterase (SR-PDE). Moreover, the compound is a potent positive inotrope both in vitro and in vivo. To assist further cardiotonic drug-design studies, we have mapped the three-dimensional structure of 1 using X-ray crystallography. From a global viewpoint, this drug was essentially planar, but two small regions of nonplanarity were apparent. These involved the geminal methyl substituents in the indol-2-one moiety and the C5' methylene unit of the dihydropyridazinone ring. Because of our previous studies involving the bipyridine cardiotonics amrinone and milrinone, the conformational relationship between the plane of the phenyl ring and the horizontal symmetry plane defined by N2', C3', and C4' of 1 was of particular interest. The C6-C5-C3'-C4' dihedral angle was -2.7 degrees, whereas the C6-C5-C3'-N2' dihedral angle was 174.6 degrees. Therefore the two rings maintain a high degree of coplanarity. Compound 4, the congener of 1 possessing a completely unsaturated pyridazinone ring was also studied. In terms of inotropic activity, this compound, devoid of any puckering in the pyridazinone moiety, was equipotent with 1. Methyl substitution at the 4-position of the dihydropyridazinone and pyridazinone rings provided disparate results. Compound 2, the 4-methyl analogue of 1, was 2-fold more potent than 1, and the methyl substituent probably caused only minor perturbations in overall molecular topology. However 5, the 4-methyl analogue of the pyridazinone 4, was 4.4-fold less active than 4, perhaps as a result of methyl-induced molecular nonplanarity.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00387a007