Identification of Isoform 2 Acid-Sensing Ion Channel Inhibitors as Tool Compounds for Target Validation Studies in CNS

Abstract

Acid-sensing ion channels (ASICs) are a family of ion channels permeable to cations and largely responsible for the onset of acid-evoked ion currents both in neurons and in different types of cancer cells, thus representing a potential target for drug discovery. Owing to the limited attention ASIC2 has received so far, an exploratory program was initiated to identify ASIC2 inhibitors using diminazene, a known pan-ASIC inhibitor, as a chemical starting point for structural elaboration. The performed exploration enabled the identification of a novel series of ASIC2 inhibitors. In particular, compound 2u is a brain penetrant ASIC2 inhibitor endowed with an optimal pharmacokinetic profile. This compound may represent a useful tool to validate in animal models in vivo the role of ASIC2 in different neurodegenerative central nervous system pathologies.

Automated Patch Clamp Screening of Amiloride and 5-N,N-Hexamethyleneamiloride Analogs Identifies 6-Iodoamiloride as a Potent Acid-Sensing Ion Channel Inhibitor

“…16 A recent phenotypic screening and medicinal chemistry optimization effort starting from diminazene described a series of dihydropyrrolo [3,4-d]pyrimidinedimethylpyrrazole inhibitors selective for ASIC2. 17 While showing only moderate potency, the lead from this series 2u 9 (ASIC2a, IC 50 = 17.4 μM), featured an excellent PK profile and high CNS penetrance. Of the small-molecule ASIC inhibitors described to date, PPC-5650 (10, core structure of class inferred from patent literature, 18 specific structure not disclosed), a potent ASIC1a-selective methylquinoline-based inhibitor is the only candidate to have progressed to clinical trials, reducing hyperalgesia readouts in Phase I studies of UVβ-induced sunburn 19 and gastroesophageal reflux disorder (GERD).…”

“…Diminazene 8 , the common livestock antiprotozoal drug, was the most potent agent identified from a screen of diarylamidine compounds, with an IC 50 of 280 nM for ASIC-mediated current in mouse primary hippocampal neurons . A recent phenotypic screening and medicinal chemistry optimization effort starting from diminazene described a series of dihydropyrrolo­[3,4- d ]­pyrimidinedimethylpyrrazole inhibitors selective for ASIC2 . While showing only moderate potency, the lead from this series 2u 9 (ASIC2a, IC 50 = 17.4 μM), featured an excellent PK profile and high CNS penetrance.…”

Automated patch clamp screening of amiloride and 5-N,N-hexamethyleneamiloride (HMA) analogs identifies 6-iodoamiloride as a potent acid-sensing ion channel inhibitor

“…16 A recent phenotypic screening and medicinal chemistry optimization effort starting from diminazene has described a series of dihydropyrrolo[3,4- d ]pyrimidinedimethylpyrrazole inhibitors selective for ASIC2. 17 While showing only moderate potency, the lead from this series 2u 9 (ASIC2a IC 50 = 17.4 μM), featured an excellent PK profile and high CNS penetrance. Of the small molecule ASIC inhibitors described to date, PPC-5650 ( 10 , core structure of class inferred from patent literature 18 , specific structure not disclosed), a potent ASIC1a-selective methylquinoline-based inhibitor is the only candidate to have progressed to clinical trials, reducing hyperalgesia readouts in Phase I studies of UVβ-induced sunburn 19 and gastroesophageal reflux disorder (GERD).…”