Pulmonary arterial hypertension (PAH), a progressive and life-threatening disease classified as a subtype of pulmonary hypertension (PH), has garnered increased attention due to its rising incidence and significant global health burden [1,2]. The distal remodeling of pulmonary arteries in PAH leads to a persistent elevation of pulmonary vascular resistance, ultimately resulting in right heart failure and premature death if left untreated [3]. The current therapeutic options for PAH treatment, involving monotherapy or combination with various vasodilator drugs [4], still have not been sufficient to improve patient prognosis in the past 20 years [5]. Recently, there has been a significant amount of research focused on discovering new targets and therapies for the treatment of PAH [3,6]. It is widely recognized that the ideal options for curative therapy in PAH aim to inhibit pulmonary vasoconstriction and pulmonary vascular remodeling [5]. In light of this, there still remains an urgent need for therapeutic targets and novel medications in the treatment of PAH.

The well-known cyclic nucleotides cAMP and cGMP, which are hydrolyzed by cyclic nucleotide phosphodiesterase (PDE) play a vital role in cardiopulmonary function, particularly in PAH. Reinforcing the NO−sGC−cGMP [7] and prostacyclin-driven cAMP signaling pathways [8] is crucial for regulating vasomotor tone, inhibiting vascular smooth muscle proliferation and fibrosis, and exerting anti-inflammatory effects to counteract pulmonary vascular remodeling [9]. Given the increasing levels of cGMP/cAMP resulting in anti-PAH effects, we attempted to investigate PDE10A with its dual specificity in cyclic nucleotide hydrolysis, which is capable of degrading both cAMP (with a Km of 56 nmol/L) and cGMP (with a Km of 4.4 μmol/L), respectively [10]. Recent studies on cardiovascular protection have elucidated that PDE10A inhibition reverses pre-established cardiac hypertrophy, fibrosis, and dysfunction [11]. Moreover, a selective PDE10A inhibitor (MP10) can suppress intimal hyperplasia partially via antagonizing synthetic smooth muscle cell (SMC) proliferation for treatment of vascular occlusive disease [12]. In addition to papaverine [13], various series of PDE10A inhibitors have shown therapeutic effects on monocrotaline (MCT)-induced PAH rats, indicating that PDE10A is a potential target for treating PAH [14,15].

The majority of reported selective PDE10A inhibitors are distinguished by their exceptional selectivity for PDE subtypes, typically exceeding 100-fold [16]. Although sildenafil, as a PDE5 inhibitor for PAH treatment exhibits excellent inhibitory efficacy (IC50 = 3.7 nmol/L), it is prone to causing vision disturbances due to its cross-reactivity with PDE6 (with only about a 16-fold selectivity). Similarly, tadalafil (IC50 = 1.8 nmol/L against PDE5) demonstrates cross-reactivity with PDE11, albeit with a relatively lower selectivity of less than 25-fold over PDE11 [17]. This advantageous characteristic of selective PDE10A inhibitors suggests a reduced risk of adverse effects resulting from inadequate selectivity towards other PDEs. Given the proven safety of PDE10A as a druggable target in clinical trials for schizophrenia and Huntington's disease [18], numerous PDE10A inhibitors have been developed to treat the central nervous system (CNS) diseases by virtue of their exceptional blood-brain barrier (BBB) permeability. However, in order to address the challenges associated with the potential inhibitory effect of selective PDE10A inhibitors on CNS caused by their accumulation in brain tissue, it is worth exploring novel selective PDE10A inhibitors with favorable drug-like properties and low BBB permeability for treating PAH.

Our previous study found that a highly selective PDE10A inhibitor 14 exhibited a significant anti-PAH curative effect at an oral single dose of 2.5 mg/kg once a day [15]. However, the drug-like characteristics of compound 14 still need to be improved to enhance metabolic stability and reduce BBB permeability. Herein, we have made continuous efforts to develop novel selective PDE10A inhibitors for the treatment of PAH in order to unveil a class of azetidine-based imidazo[1,2-a]pyridine compounds. Among them, compound A30 exhibited a potent IC50 value of 3.5 nmol/L against PDE10A, demonstrating high selectivity towards other PDEs and favorable metabolic stability in rat liver microsomes (RLMs). The improved drug-like properties of A30 underscored its potential applicability for peripheral tissue diseases, particularly by mitigating BBB permeability and cytochrome P450 (CYP450) inhibition (Fig. 1). Importantly, A30 significantly reduced the mean pulmonary artery pressure (mPAP) and right ventricular (RV) hypertrophy, and improved pulmonary artery thickness in vivo when administered at a single daily dosage of 2.5 mg/kg (p.o.) in two distinct classic animal models induced by MCT and Sugen/hypoxia, respectively.