Discovery and Optimization of Chromeno[2,3-c]pyrrol-9(2H)-ones as Novel Selective and Orally Bioavailable Phosphodiesterase 5 Inhibitors for the Treatment of Pulmonary Arterial Hypertension

Abstract

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.

A Multi-Biochemical and In Silico Study on Anti-Enzymatic Actions of Pyroglutamic Acid against PDE-5, ACE, and Urease Using Various Analytical Techniques: Unexplored Pharmacological Properties and Cytotoxicity Evaluation

“…Numerous studies have conveyed severe side effects of these inhibitors, especially with sildenafil, where the problems with vision disturbance, hearing loss, and headache were claimed [35,36]. Therefore, there is an urgent need to explore novel, selective, and effective PDE-5 inhibitors with reduced adverse effects to overcome such complications [37]. To the best of our knowledge, this is a first study on the inhibition efficacy of pGlu against PDE-5.…”

Total Synthesis of Mulberry Diels–Alder-Type Adducts Kuwanons G and H

“…15 Iodoflavonoid 10 could be sourced from 11 via alkylation of β-diketone and intramolecular cyclization, while the β-diketone 11 could be prepared from commercially available 12 and 13. 16 As the dienophile of MDAAs, chalcone and its derivatives could be easy furnished followed the established route. 14 As shown in Scheme 2, the Claisen−Schmidt condensation of 4′methoxy-2′-hydroxyacetophenone 8 and 2,4-dimethoxybenzaldehyde 9 occurred smoothly in the presence of NaOH to generate the dienophile 6.…”

“…The dehydroprenyl moiety of prenylated dehydroprenylflavonoid 5 could be introduced by the Suzuki–Miyaura coupling reaction of the corresponding intermediate 10 . Iodoflavonoid 10 could be sourced from 11 via alkylation of β-diketone and intramolecular cyclization, while the β-diketone 11 could be prepared from commercially available 12 and 13 …”

Discovery of catalytic-site-fluorescent probes for tracing phosphodiesterase 5 in living cells

“…In our previous work, we discovered a series of PDE5 inhibitors with chromeno[2,3-c]pyrrol-9(2H)-one as the skeleton, which exhibited extraordinary inhibition towards PDE5. 21,22 Surprisingly, LW1607, one of such PDE5 inhibitors, was capable of emitting blue uorescence under the excitation at 365 nm. However, the capability of LW1607 for uorescent imaging is still limited by the short-wavelength uorescent emission and weak uorescence intensity (Table S1, ESI †).…”