Inhibitors of Blood Platelet cAMP Phosphodiesterase. 3. 1,3-Dihydro-2H-imidazoquinolin-2-one Derivatives with Enhanced Aqueous Solubility

Article abstract of DOI:10.1021/jm00092a020

Two series of 1,3-dihydro-2H-imidazo<4,5-b>quinolin-2-one derivatives incorporating an additional site for acid salt formation were synthesized and evaluated as inhibitors of human blood platelet cAMP phosphodiesterase (PDE) and ADP-induced platelet aggregation.The objective of this study was to identify compounds that blended potent biological activity with a satisfactory level of aqueous solubility.From a series of 7-aminoimidazo<4,5-b>quinolin-2-ones, biological and physical properties were optimally combined in the 1-piperidinyl derivative 11c.However, this compound offered no significant advantage over earlier studied compounds as an antithrombotic agent in an animal model of small vessel thrombosis.A series of 7-alkoxy alkanoic piperazinamide derivatives, in which the additional basic nitrogen atom was remote from the heterocyclic nucleus and accomodated in a secondary binding region of the cAMP PDE enzyme, demonstrated greater intrinsic cAMP PDE inhibitory activity.Structural modifications of this series focused on variation of the piperazine substituent and side-chain length.The lipophilicity of the N-substituent influenced biological potency and aqueous solubility, with substituents of seven carbon atoms or less generally providing acceptable solubility properties.The N-(cyclohexylmethyl)piperazinamide 21h was identified from this series of compounds as a potent inhibitor of platelet cAMP PDE, IC50 = 0.4 nM and ADP-induced platelet aggregation, IC50 = 0.51 μM after a 3-min exposure and 0.1 μM after a 15-min exposure of platelet-rich plasma to the drug.Evaluation of 21h and representative analogues in vivo using a rabbit model of small vessel thrombosis revealed significantly greater antithrombotic efficacy compared to that of previously studied compounds with similar intrinsic biological activity measured in vitro but inferior aqueous solubility.