Aprocitentan

Aprocitentan, sold under the brand name Tryvio (Idorsia), is a medication used for the treatment of hypertension (high blood pressure). It has been approved by the FDA to treat hypertension in combination with other antihypertensive medications in adults who can’t adequately control their blood pressure with existing therapies. Aprocitentan is an endothelin receptor antagonist that inhibits the binding of endothelin (ET)-1 to ETA and ETB receptors. The effects of ET-1 bear many similarities with the pathophysiology of hypertension, and ET-1 is a major driver of aldosterone production. Until the approval of TRYVIO, no systemic antihypertensive medications targeted the ET pathway, as approved antihypertensive therapies focus on the regulation of salt and water (diuretics), antagonism of the renin–angiotensin–aldosterone (RAAS) system, reduction of influx of extracellular calcium into the cell (calcium channel blockers), sympatholytic activity (beta blockers, central alpha-agonist agents), or non-selective vasodilatory effects.

Idorsia was formed through a spinoff after J&J’s $30 billion buyout of Actelion in 2017. The Swiss biotech started off with CHF 1 billion (about $1 billion) in cash — funded by Actelion and a J&J affiliate — and a fairly robust pipeline of early- to mid-stage drugs. A few months later, J&J acquired rights to aprocitentan, offering an initial payment of $230 million, development funds and potential royalties. Idorsia also got to share revenue from a J&J drug for multiple sclerosis now sold as Ponvory. That agreement will also end with the return of rights to aprocitentan.
A few months back, before its approval, J&J’s decided to pull back from aprocitentan deal, in another series of setbacks for Idorsia, whose shares are trading at all-time lows. As part of the deal, Idorsia will pay J&J as much as 306 million Swiss francs, or about $343 million, to reacquire rights to the drug. The total amount depends on regulatory approvals, potential future licenses and commercial sales. J&J will retain rights to aprocitentan for pulmonary hypertension. The reacquisition of aprocitentan is expected to provide a much-needed boost to Idorsia’s profits. GlobalData forecasts aprocitentan to generate $241m in sales in 2029.

The first synthetic patent for Aprocitentan dates from 2009 and was originated by Acetilon Pharmaceuticals. It starts with the formation of the methyl ester 2, from the reaction of (4-bromophenyl)acetic acid (1) with MeOH in the presence of SOCl2. Claisen condensation with dimethyl carbonate by means of NaH in THF affords the dimethyl malonate derivative 3. Cyclization of diester 3 with formamidine hydrochloride in the presence of NaOMe in MeOH generates diol 4, which is then chlorinated using POCl3 in the presence of DMA at 130 °C to produce 5-(4-bromophenyl)-4,6-dichloropyrimidine (5). Reaction of 5 with potassium benzylsulfamide (6) in the presence of DMSO at 60 °C yields sulfamide 7.