BMY21190, A Potent Inhibitor of cAMP Phosphodiesterase

A number of compounds capable of inhibiting the aggregation of blood platelets have been reported in recent years. Synthesized compounds containing the imidazo [4,5-b] quinoline-Zone nucleus are a new series of structurally-novel inhibitors of platelet aggregation (38). These compounds are potent broad-spectrum inhibitors that inhibit platelet aggregation caused by thrombin, ADP, and collagen with roughly equal potency (8,15). BMY21190 (Fig. 1) inhibits ADPand collagen-induced aggregation of rabbit platelets with an efficacy comparable to prostacyclin (38). BMY21190 may also be capable of elevating the cAMP levels within platelets sufficiently to activate the CAMP-dependent protein kinase as does BMY20844 (60, Fig. 1). The active catalytic subunit is released by the binding of cAMP to the regulatory subunit of the protein kinase and then acts at many different steps in the biochemical pathways to inhibit platelet inhibition (13,58,59). Agents that elevate platelet cAMP levels, including inhibitors of platelet cAMP phosphodiesterase (PDE) (2,23,38,46,65), are known to inhibit platelet aggregation (21,38, 40). Platelet aggregation is generally regarded as an important event in the initiation of arterial thrombosis. The current interest in inhibitors of CAMP-PDE as therapeutic agents has largely arisen from the recognition that there are distinct PDE isozyme families and that tissues have different complements of isozymes. Nomenclature and subcellular localization of CAMP-PDE isozymes are to be found in articles from Beavo’s (4,28) and Weishaar’s laboratories (67,68). BMY20844 and BMY21190 have the characteristics of selective type I11 inhibitors of “low Km” one of which is high affinity for cAMP (38). The CAMP-PDE type 111 isozyme has been isolated from or found in platelets (17,46), cytosolic fractions of bovine cardiac tissue (19), and