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

Abstract

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.

Identification of Interaction Sites of Cyclic Nucleotide Phosphodiesterase Type 3A with Milrinone and Cilostazol Using Molecular Modeling and Site-Directed Mutagenesis

“…As competitive inhibitors, milrinone and cilostazol should directly compete with the substrates for the binding site in the active site of PDE3A. Our data are consistent with a competitive inhibitory mechanism for both milrinone and cilostazol (Robertson et al, 1987). Fig.…”

Calcium Sensitizing and Phosphodiesterase-III Inhibitory Activity of Pyridazine Compounds: A Review

“…The geminal methyl substituents in the indol-2-one ring and the C5' methylene unit of the dihydro pyridazinone ring. The 4-methyl analogue of LY195115, was 2-fold more potent activity than LY195115, and the methyl substituent maybe caused minor perturbations in general molecular topology [87]. Pharmacological effects of the 4-ethoxy-2-methyl-5morpholino-3(2H)-pyridazinone (M73101) is a nonsteroidal anti-inflammatory drug (NSAID), i.v.…”

Design, synthesis and antihypertensive screening of novel pyridazine substituted s-triazin-2-imine/one/thione derivatives

“…Pyridazines are important biologically active scaffolds, possessing antihypertensive 4 , cardiotonic 5 , analgesic 6 , anti-inflammatory 7 , antidepressant 8 , antibacterial 9 , anticancer 10 , nephrotopic drugs 11 , antithrombic 12 , diuretic 13 and anti-HIV 14 activities. Some pyridazine derivatives, such as bemoradan 15 , indolidan 16 , levosimendan 17 , pimobendan 18 , zardaverine 19 and imazodan 20 , have already appeared in the clinical market. Nitrogen containing heterocycles play an important role not only for life science industry but also in many other industrial fields related to special and fine chemistry.…”