PBF-680, an oral A1 adenosine receptor antagonist, inhibits the late allergic response (LAR) in mild-to-moderate atopic asthmatics: a Phase-IIa trial

Optimization of 2-Amino-4,6-diarylpyrimidine-5-carbonitriles as Potent and Selective A1 Antagonists

“…Among these ligands, 19ao (Figure , purple square) stands out as the most attractive A 1 AR antagonist identified during this study, combining high potency ( K i = 6.11 nM) with excellent selectivity toward the rest of the ARs (Table ). It should be noticed that, in addition to its 2-methylamino group at 2, 19ao contains a piperonyl group at R 4 , a relatively frequent motif within A 1 AR antagonists. − Further introduction of pentagonal or hexagonal heterocyclic moieties at R 4 enabled the identification of three potent and selective A 1 AR ligands ( 19az , 19bb , and 19bd ) that combine 3-thienyl, 4-pyridyl, or 3-pyridyl groups at R 4 with an exocyclic methylamino group in R 2 ( K i = 42.8, 56.9, and 19.3 nM, respectively). Interestingly, pyrimidine derivatives bearing 3-thienyl or 3-furyl substituents at R 4 and an N -phenylamino at R 2 exhibit moderate affinity ( K i = 368 and 102 nM, respectively) and complete selectivity toward the A 2A AR.…”

“… 19 Currently, the only A 1 AR antagonist in clinical studies is PBF-680 (structure not disclosed), which is undergoing phase II as a peripheral selective oral treatment for respiratory diseases (asthma and COPD). 20 , 21 …”

“…In particular, A 1 AR antagonists have been proposed as effective potassium-sparing diuretic agents with kidney protecting properties . Currently, the only A 1 AR antagonist in clinical studies is PBF-680 (structure not disclosed), which is undergoing phase II as a peripheral selective oral treatment for respiratory diseases (asthma and COPD). , …”

“…The therapeutic applications emerging from A 1 AR modulation stimulated the development of several series of small molecule A 1 AR ligands. − From these, A 1 AR antagonists can be classified in two structural families: xanthines and non-xanthines (Figure ). The discovery that naturally occurring alkylxanthines (e.g., caffeine, theophylline, and theobromine) are micromolar (non-selective) AR antagonists inspired extensive pharmacomodulation of the xanthine moiety, thus culminating with the identification of potent and selective A 1 AR, A 2A AR, and A 2B AR antagonists.…”

“…The discovery that naturally occurring alkylxanthines (e.g., caffeine, theophylline, and theobromine) are micromolar (non-selective) AR antagonists inspired extensive pharmacomodulation of the xanthine moiety, thus culminating with the identification of potent and selective A 1 AR, A 2A AR, and A 2B AR antagonists. Xanthine-based A 1 AR antagonists generally contain a bulky hydrophobic group at position 8 and alkyl chains at positions 1 and 3 (Figure , Cpds 1 – 6 ). ,− Despite possessing excellent affinity and subtype selectivity, the advancement of xanthine-based A 1 AR antagonists as drug candidates has been hampered by their poor bioavailability and low water solubility, narrow efficacy, and off-target effects. − Efforts to identify non-xanthine A 1 AR antagonists mostly focused on bicyclic scaffolds that somehow mimic the adenine core present in the endogenous ligand (adenosine) and, to a lesser extent, tricyclic (Figure , Cpds 7 and 8 ) , and monocyclic systems (Figure , Cpds 9 – 11 ). − However, the high structural homology between the A 1 AR and A 2A AR, particularly in the orthosteric site, has limited the development of A 1 AR antagonists exhibiting both high affinity and selectivity against the A 2A AR. Thus, only a few truly selective monocyclic A 1 AR antagonists have been described so far, with representative examples based on the thiazole and pyrimidine cores (Figure , Cpds 12 – 14 ). , It follows that the identification of highly potent and selective structurally simple A 1 AR antagonists remains a challenging goal.…”