sildenafil and Hypertension--Pulmonary

Current pulmonary arterial hypertension (PAH) therapeutic strategies mainly focus on vascular relaxation with less emphasis on vascular remodeling, which results in poor prognosis. Hence, dual pathway regulators with vasodilation effect via soluble guanylate cyclase (sGC) stimulation and vascular remodeling regulation effect by AMP-activated protein kinase (AMPK) inhibition provide more advantages and potentialities. Herein, we designed and synthesized a series of novel pyrazolo[3,4-

Topics: Adenylate Kinase; Animals; Cell Line; Drug Design; Humans; Hypertension, Pulmonary; Pyrazoles; Pyridines; Rats; Structure-Activity Relationship; Vascular Remodeling; Vasodilation

Phosphodiesterase type 5 (PDE5) inhibitors are first-line therapy for pulmonary arterial hypertension (PAH) and erectile dysfunction. As a continuing work to improve the terminal half-lives and oral bioavailabilities of our previously reported 4(3 H)-pyrimidones, a pharmacokinetics-driven optimization focusing on the terminal substituent is described. Two major congeneric series of 4(3 H)-pyrimidones, the aminosulfonylphenylpyrimidones and acylaminophenylpyrimidones, were designed, synthesized, and pharmacologically assessed in vitro and in vivo. Among them, compound 15 (TPN171) with subnanomolar potency for PDE5 and good selectivity over PDE6 was finally recognized as a potential drug candidate, and its pharmacokinetic profiles in rats and dogs are significantly improved compared to the starting compound (3). Moreover, TPN171 was proven to exert a longer lasting effect than sildenafil in animal models, providing a foundation for a once-daily oral administration for its clinical use. TPN171 is currently being investigated in a phase II clinical trial for the treatment of PAH.

Topics: Animals; Dogs; Drug Design; Female; Half-Life; Hypertension, Pulmonary; Male; Phosphodiesterase 5 Inhibitors; Pyrimidines; Rats; Rats, Inbred SHR; Rats, Sprague-Dawley; Sildenafil Citrate; Structure-Activity Relationship; Substrate Specificity

Topics: Administration, Oral; Animals; Crystallography, X-Ray; ERG1 Potassium Channel; Hypertension, Pulmonary; Microsomes, Liver; Models, Molecular; Molecular Structure; Phosphodiesterase 5 Inhibitors; Protein Conformation; Pulmonary Artery; Structure-Activity Relationship

Phosphodiesterase 5 (PDE5) inhibitors have been used as clinical agents to treat erectile dysfunction and pulmonary arterial hypertension (PAH). Herein, we detail the discovery of a novel series of chromeno[2,3-c]pyrrol-9(2H)-one derivatives as selective and orally bioavailable inhibitors against phosphodiesterase 5. Medicinal chemistry optimization resulted in 2, which exhibits a desirable inhibitory potency of 5.6 nM with remarkable selectivity as well as excellent pharmacokinetic properties and an oral bioavailability of 63.4%. In addition, oral administration of 2 at a dose of 5.0 mg/kg caused better pharmacodynamics effects on both mPAP (mean pulmonary artery pressure) and RVHI (index of right ventricle hypertrophy) than sildenafil citrate at a dose of 10.0 mg/kg. These activities along with its reasonable druglike properties, such as human liver microsomal stability, cytochrome inhibition, hERG inhibition, and pharmacological safety, indicate that 2 is a potential candidate for the treatment of PAH.

Topics: Animals; Catalytic Domain; CHO Cells; Chromones; Cricetulus; Cytochrome P-450 CYP1A2 Inhibitors; Drug Stability; ERG1 Potassium Channel; Female; Humans; Hypertension, Pulmonary; Male; Mice; Microsomes, Liver; Molecular Docking Simulation; Molecular Dynamics Simulation; Phosphodiesterase 5 Inhibitors; Pyrroles; Rats, Sprague-Dawley; Rats, Wistar; Sildenafil Citrate; Structure-Activity Relationship