The design and synthesis of selective activators of Adenylyl Cyclase isoform 6 for the treatment of persistent pulmonary hypertension of the newborn

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Pritchard, Alexander
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Persistent Pulmonary Hypertension of the Newborn (PPHN), is a condition that reduces relaxation of blood vessels, which prevents a normal transition to independent breathing from occurring. This leads to hypoxia and if untreated can be fatal. Under these conditions an enzyme known as adenylyl cyclase (AC) has decreased activity, AC isoform 6 is associated with vasodilation, and if activated could produce a vasodilation effect. This would allow blood vessels to relax and breathing to return to normal. Forskolin, a natural product from plants, can activate all nine transmembrane isoforms of AC, if forskolin was given as a treatment for PPHN, it could activate AC6, causing vasodilation, returning breathing and blood oxygen levels to normal. Unfortunately, forskolin does not activate AC6 specifically, and activating all isoforms of AC would cause side effects throughout the body and may make the condition worse. Previously forskolin has been successfully derivatised to selectively activate different isoforms of AC, AC2 and AC5, similar studies have not been completed for AC6, however, this previous work suggests that increasing isoform selectivity is possible. In this project derivatives of forskolin will be synthesized in an attempt to create an AC6 isoform-specific activator, this could drug molecule could potentially be used to treat PPHN.
Natural Product Chemistry, Medicinal Chemistry