INVOLVEMENT OF CYCLIC GMP IN THE MODE OF ACTION OF A NEW ANTITHROMBOTIC AGENT PCA-4230; INHIBITION OF THE PLATELET CYCLIC GMP DEPENDENT PHOSPHODIESTERASE

Q3 · MEDICINE

Article

Author: Ana M. Martínez ; R.Edgardo Catalán ; Manuel Lombardía ; M.Dolores Aragonés

The effect of PCA-4230, a new dihydropyridine derivative with a potent antithrombotic activity, on cyclic nucleotide phosphodiesterase in platelets was studied. PCA-4230 inhibited (54%) cyclic GMP hydrolytic activity of a platelet cytosolic fraction, whereas it did not affect that of cyclic AMP. Results suggested that PCA-4230 inhibited a cyclic GMP-dependent phosphodiesterase, known as cGB PDE or type V, on a purified enzyme from rabbit platelets by a non-competitive-uncompetitive type inhibition. In addition, PCA-4230 potentiated the increase in both cyclic GMP and cyclic AMP levels evoked by sodium nitroprusside. Furthermore, PCA-4230 and forskolin caused a synergistic effect in cyclic AMP, and also potentiated the phosphorylation of 50 kDa and 22 kDa proteins, reported as substrates of cyclic GMP- and cyclic AMP-dependent protein kinases that are related to the inhibition of platelet functions. Finally, PCA-4230 also potentiated the forskolin- and sodium nitroprusside-inhibited serotonin release evoked by thrombin, probably related to the increased cyclic nucleotide level.

01 Jul 1994·Thrombosis ResearchQ3 · MEDICINE

Dissociation between secretion and protein phosphorylation in agonist-stimulated platelets; action of PCA-4230, a new antithrombotic drug

Q3 · MEDICINE

Article

Author: Ana M. Martinez ; R.Edgardo Catalán ; Félix Hernández ; Manuel Lombardia ; Esther Garde ; M.Dolores Aragonés

We have studied the effects of PCA-4230, a new dihydropyridine derivative with antithrombotic activity, on the secretion of dense and alpha-granules from platelets and on the protein phosphorylation in platelets after stimulation by agonists. The drug prevented both dense and alpha-granule secretion evoked by thrombin, platelet-activating factor (PAF) and ionophore A23187, the former secretion being more sensitive than the latter one to the PCA-4230 action. These inhibitory effects on secretion processes did not correlate with the differential action of PCA-4230 on protein phosphorylation. Thus, the 40 kDa protein phosphorylation evoked by thrombin was potentiated whereas that elicited by ionophore A23187 was partially inhibited. The 20 kDa protein phosphorylation was practically insensitive to the drug action. These data, together with previous evidence reported by us on PCA-4230, lead us to suggest the existence of a common and critical step for platelet secretion evoked by agonists with different signal transduction pathways.

01 Jul 1993·Journal of Photochemistry and Photobiology B: BiologyQ2 · BIOLOGY

New 4-alkyl-1,4-dihydropyridines: Evaluation of photostability and phototoxic potential

Q2 · BIOLOGY

Article

Author: C. Sunkel ; C. Glena ; A.M. Cárdenas ; M.P. Cortés ; M.E. Hidalgo ; E. Fernández

The photostability and phototoxic potential of two new 4-alkyl-1,4-dihydropyridines (PCA-4230 and PCA-4248) were investigated. When these 4-alkyl-1,4-dihydropyridines were irradiated with a multilamp photoreactor (band centred at 350 nm), both exhibited a slow photodegradation showing first-order kinetics. The photodegradation rate constants were 0.37 h-1 for PCA-4248 and 0.39 h-1 for PCA-4230 in oxygenated conditions. The photodecomposition was slower for both drugs in the absence of oxygen. In order to evaluate the phototoxicity induced by these drugs, red blood cells and Hep-2 (human laringo carcinoma cell line) were irradiated using a minisolarium, which emits UVA radiation (350-390 nm). The results showed that PCA-4248 and PCA-4230 did not exhibit a phototoxic effect in the two models tested.

100 Deals associated with Trombodipine

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Indication	Highest Phase	Country/Location	Organization	Date
Arterial Occlusive Diseases	Phase 2	-	Alter Ltd.	-
Arterial Occlusive Diseases	Phase 2	CL	-	-
Myocardial Ischemia	Phase 2	-	Alter Ltd.	-
Myocardial Ischemia	Phase 2	ES	-	-
Thrombosis	Phase 2	ES	-	-
Thrombosis	Phase 2	CL	-	-
Thrombosis	Phase 2	DE	-	-
Thrombosis	Phase 2	-	Alter Ltd.	-
Arterial Occlusive Diseases	Phase 1	DE	-	-

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