ABSTRACT
Pulmonary arterial hypertension (PAH) is a severe disease characterised by increased pulmonary vascular resistance, which leads to restricted pulmonary arterial blood flow and elevated pulmonary arterial pressure. In patients with PAH, pulmonary concentrations of prostacyclin, a prostanoid that targets several receptors including the IP prostacyclin receptor, are reduced. To redress this balance, epoprostenol, a synthetic prostacyclin, or analogues of prostacyclin have been given therapeutically. These therapies improve exercise capacity, functional class and haemodynamic parameters. In addition, epoprostenol improves survival among patients with PAH. Despite their therapeutic benefits, treatments that target the prostacyclin pathway are underused. One key factor is their requirement for parenteral administration: continuous intravenous administration can lead to embolism and thrombosis; subcutaneous administration is associated with infusion-site pain; and inhalation is time consuming, requiring multiple daily administrations. Nevertheless, targeting the prostacyclin pathway is an important strategy for the management of PAH. The development of oral therapies for this pathway, as well as more user-friendly delivery devices, may alleviate some of the inconveniences. Continued improvements in therapeutic options will enable more patients with PAH to receive medication targeting the prostacyclin pathway.
Subject(s)
Antihypertensive Agents/therapeutic use , Arterial Pressure/drug effects , Hypertension, Pulmonary/drug therapy , Prostaglandins I/therapeutic use , Pulmonary Artery/drug effects , Vasodilator Agents/therapeutic use , Administration, Inhalation , Administration, Oral , Antihypertensive Agents/administration & dosage , Antihypertensive Agents/adverse effects , Antihypertensive Agents/chemical synthesis , Humans , Hypertension, Pulmonary/diagnosis , Hypertension, Pulmonary/metabolism , Hypertension, Pulmonary/physiopathology , Infusions, Parenteral , Molecular Targeted Therapy , Prostaglandins I/administration & dosage , Prostaglandins I/adverse effects , Prostaglandins I/chemical synthesis , Pulmonary Artery/metabolism , Pulmonary Artery/physiopathology , Receptors, Epoprostenol/drug effects , Receptors, Epoprostenol/metabolism , Severity of Illness Index , Signal Transduction/drug effects , Treatment Outcome , Vasodilator Agents/administration & dosage , Vasodilator Agents/adverse effects , Vasodilator Agents/chemical synthesisABSTRACT
A general and novel solution to the synthesis of biologically important stable analogues of prostacyclin PGI(2), namely benzindene prostacyclins, has been achieved via the stereoselective intramolecular Pauson-Khand cyclization (PKC). This work illustrates for the first time the synthetic utility and reliability of the asymmetric PKC route for synthesis and subsequent manufacture of a complex drug substance on a multikilogram scale. The synthetic route surmounts issues of individual step stereoselectivity and scalability. The key step in the synthesis involves efficient stereoselection effected in the PKC of a benzoenyne under the agency of the benzylic OTBDMS group, which serves as a temporary stereodirecting group that is conveniently removed via benzylic hydrogenolysis concomitantly with the catalytic hydrogenation of the enone PKC product. Thus the benzylic chiral center dictates the subsequent stereochemistry of the stereogenic centers at three carbon atoms (C(3a), C(9a), and C(1)).
