Pharmacokinetics-Driven Optimization of 4(3H)-Pyrimidinones as Phosphodiesterase Type 5 Inhibitors Leading to TPN171, a Clinical Candidate for the Treatment of Pulmonary Arterial Hypertension

Abstract

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(3H)-pyrimidones, a pharmacokineticsdriven optimization focusing on the terminal substituent is described. Two major congeneric series of 4(3H)-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.

Challenges on Cyclic Nucleotide Phosphodiesterases Imaging with Positron Emission Tomography: Novel Radioligands and (Pre-)Clinical Insights since 2016

“…In 2017, Chekol et al [72] reported on two novel PDE5-specific radioligands, [ 11 C]15 and [ 18 F]16 (see Figure 4), for evaluation of the enzyme expression and occupancy in lung, heart and brain by PET. [76,77]as well as the PDE5 inhibitors tadalafil [78,79], vardenafil [78,80] and sildenafil [78][79][80].…”

“…Out of a series of pyridopyrazinone derivatives, compounds 15 and 16 showed highest inhibitory potency towards PDE5 (Figure 4) and were subsequently selected for radiolabeling. Starting from the corresponding desmethyl or tosylate precursors, [ 11 [76,77]as well as the PDE5 inhibitors tadalafil [78,79], vardenafil [78,80] and sildenafil [78][79][80].…”

“…Besides, Xu et al [77] reported on the development of [ 11 C]21 for PET imaging of PDE5 in the heart. Briefly, the 4(3H)-pyrimidine lead compound 21 has previously been developed by Wang et al [76] as highly potent PDE5 inhibitor (Figure 4) for the treatment of pulmonary arterial hypertension and is currently being investigated in a phase II clinical trial.…”

“…Figure 4. Molecular structures and IC 50 values for PDE5 of ([ 11 C])15 and ([ 18 F])16 [72], ([ 18 F])17 [73] and ([ 18 F])18 [74], ([ 11 C])19 and ([ 11 C])20 [75], ([ 11 C])21[76,77]as well as the PDE5 inhibitors tadalafil[78,79], vardenafil[78,80] and sildenafil[78][79][80].…”

A Phase I Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of TPN171H, a Novel Phosphodiesterase Type 5 Inhibitor, in Healthy Subjects

“…12 In preclinical experiments, TPN171H was proved to have good selectivity, exhibit satisfactory safety and pharmacokinetic profiles in rats and dogs, and exert a longer-lasting effect than sildenafil in animal models. 13 Therefore, we conducted this study to evaluate the safety, tolerability, and pharmacokinetics of TPN171H in healthy subjects after single and multiple dosing, in addition, to investigate the food effect on pharmacokinetics and safety of TPN171H.…”