Pharmacokinetics, mass balance, and metabolism of [14C]TPN171, a novel PDE5 inhibitor, in humans for the treatment of pulmonary arterial hypertension

He, Yurong; Liu, Yin; Yu, Jinghua; Cheng, Hui; Odilov, Abdullajon; Yang, Feipu; Tian, Guanghui; Yao, Xiu-Mei; Duan, Huaqing; Yu, Chengyin; Chen, Yu; Liu, Yanmei; Liu, Gangyi; Shen, Jingshan; Wang, Zhen; Diao, Xingxing

doi:10.1038/s41401-022-00922-6

Cited by 7 publications

(2 citation statements)

References 39 publications

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“…In vitro experiments revealed that its PDE5 inhibitory activity was stronger than sildenafil and tadalafil. Phase-1b clinical trials have been completed with good safety and tolerability [ 113 , 114 , 115 ], and a phase-2a multicenter, randomized, placebo- and positive-controlled study (NCT04483115) is ongoing to assess its acute hemodynamic effects in PAH patients.…”

Section: Potential Drugs Being Investigatedmentioning

confidence: 99%

Medical Management of Pulmonary Arterial Hypertension: Current Approaches and Investigational Drugs

et al. 2023

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Pulmonary arterial hypertension (PAH) is a malignant pulmonary vascular syndrome characterized by a progressive increase in pulmonary vascular resistance and pulmonary arterial pressure, which eventually leads to right heart failure and even death. Although the exact mechanism of PAH is not fully understood, pulmonary vasoconstriction, vascular remodeling, immune and inflammatory responses, and thrombosis are thought to be involved in the development and progression of PAH. In the era of non-targeted agents, PAH had a very dismal prognosis with a median survival time of only 2.8 years. With the deep understanding of the pathophysiological mechanism of PAH as well as advances in drug research, PAH-specific therapeutic drugs have developed rapidly in the past 30 years, but they primarily focus on the three classical signaling pathways, namely the endothelin pathway, nitric oxide pathway, and prostacyclin pathway. These drugs dramatically improved pulmonary hemodynamics, cardiac function, exercise tolerance, quality of life, and prognosis in PAH patients, but could only reduce pulmonary arterial pressure and right ventricular afterload to a limited extent. Current targeted agents delay the progression of PAH but cannot fundamentally reverse pulmonary vascular remodeling. Through unremitting efforts, new therapeutic drugs such as sotatercept have emerged, injecting new vitality into this field. This review comprehensively summarizes the general treatments for PAH, including inotropes and vasopressors, diuretics, anticoagulants, general vasodilators, and anemia management. Additionally, this review elaborates the pharmacological properties and recent research progress of twelve specific drugs targeting three classical signaling pathways, as well as dual-, sequential triple-, and initial triple-therapy strategies based on the aforementioned targeted agents. More crucially, the search for novel therapeutic targets for PAH has never stopped, with great progress in recent years, and this review outlines the potential PAH therapeutic agents currently in the exploratory stage to provide new directions for the treatment of PAH and improve the long-term prognosis of PAH patients.

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Section: Potential Drugs Being Investigatedmentioning

confidence: 99%

Medical Management of Pulmonary Arterial Hypertension: Current Approaches and Investigational Drugs

et al. 2023

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“…However, the authors did not perform a biodistribution study or an in vitro assessment of tracer inhibitory activity to ensure that the radiotracer’s binding ability to PDE5 was unaffected [ 277 ]. Very recently, a 14 C-radiolabeled derivative of ( 2 ) was used to assess its pharmacokinetics where ( 2 ) exhibited rapid absorption in humans ( T max = 0.67 h) and t 1/2 of 9.9 h, besides extensive metabolism into 22 metabolites in human plasma, urine and feces [ 278 ].…”

Section: Pde5 Inhibitorsmentioning

confidence: 99%

Advancements in Phosphodiesterase 5 Inhibitors: Unveiling Present and Future Perspectives

ElHady,

El-Gamil,

Abdel-Halim

et al. 2023

Pharmaceuticals

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Phosphodiesterase 5 (PDE5) inhibitors presented themselves as important players in the nitric oxide/cGMP pathway, thus exerting a profound impact on various physiological and pathological processes. Beyond their well-known efficacy in treating male erectile dysfunction (ED) and pulmonary arterial hypertension (PAH), a plethora of studies have unveiled their significance in the treatment of a myriad of other diseases, including cognitive functions, heart failure, multiple drug resistance in cancer therapy, immune diseases, systemic sclerosis and others. This comprehensive review aims to provide an updated assessment of the crucial role played by PDE5 inhibitors (PDE5-Is) as disease-modifying agents taking their limiting side effects into consideration. From a medicinal chemistry and drug discovery perspective, the published PDE5-Is over the last 10 years and their binding characteristics are systemically discussed, and advancement in properties is exposed. A persistent challenge encountered with these agents lies in their limited isozyme selectivity; considering this obstacle, this review also highlights the breakthrough development of the recently reported PDE5 allosteric inhibitors, which exhibit an unparalleled level of selectivity that was rarely achievable by competitive inhibitors. The implications and potential impact of these novel allosteric inhibitors are meticulously explored. Additionally, the concept of multi-targeted ligands is critically evaluated in relation to PDE5-Is by inspecting the broader spectrum of their molecular interactions and effects. The objective of this review is to provide insight into the design of potent, selective PDE5-Is and an overview of their biological function, limitations, challenges, therapeutic potentials, undergoing clinical trials, future prospects and emerging uses, thus guiding upcoming endeavors in both academia and industry within this domain.

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Pharmacokinetics, Mass Balance and Metabolism of [14C]HSK21542, a Novel Kappa Opioid Receptor Agonist, in Humans

Yuan,

Bian,

et al. 2023

Eur J Drug Metab Pharmacokinet

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Pharmacokinetics, mass balance, and metabolism of [14C]TPN171, a novel PDE5 inhibitor, in humans for the treatment of pulmonary arterial hypertension

Cited by 7 publications

References 39 publications

Medical Management of Pulmonary Arterial Hypertension: Current Approaches and Investigational Drugs

Medical Management of Pulmonary Arterial Hypertension: Current Approaches and Investigational Drugs

Advancements in Phosphodiesterase 5 Inhibitors: Unveiling Present and Future Perspectives

Pharmacokinetics, Mass Balance and Metabolism of [14C]HSK21542, a Novel Kappa Opioid Receptor Agonist, in Humans

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