In this Letter we report on the advances in our NPBWR1 antagonist program aimed at optimizing the 5-chloro-2-(3,5-dimethylphenyl)-4-(4-methoxyphenoxy)pyridazin-3(2H)-one lead molecule previously obtained from a high-throughput screening (HTS)-derived hit. Synthesis and structure-activity relationships (SAR) studies around the 3,5-dimethylphenyl and 4-methoxyphenyl regions resulted in the identification of a novel series of non-peptidic submicromolar NPBWR1 antagonists based on a 5-chloro-4-(4-alkoxyphenoxy)-2-(benzyl)pyridazin-3(2H)-one chemotype. Amongst them, 5-chloro-2-(9H-fluoren-9-yl)-4-(4-methoxyphenoxy)pyridazin-3(2H)-one 9h (CYM50769) inhibited NPW activation of NPBWR1 with a submicromolar IC(50), and displayed high selectivity against a broad array of off-targets with pharmaceutical relevance. Our medicinal chemistry study provides innovative non-peptidic selective NPBWR1 antagonists that may enable to clarify the biological role and therapeutic utility of the target receptor in the regulation of feeding behavior, pain, stress, and neuroendocrine function.
[Show abstract][Hide abstract] ABSTRACT: Neuropeptide B/W receptor 1 (NPBWR1), previously known as G-protein coupled receptor 7 (GPR7), is a class A G-protein coupled receptor implicated in the modulation of several neuroendocrine functions such as feeding behavior, energy homeostasis, epilepsy, and analgesia. In recent years, a few antagonists have been designed that bind to NPBWR1 with high affinity. However, the exact binding modes between the antagonists and the receptor are still unknown. Unraveling the key pharmacophoric features of the receptor will guide the development of novel compounds with increased potency for therapeutic use. Here, we studied the structural organization of NPBWR1 receptor and its antagonist binding modes through computational approaches. Based on the dynamics and energetic features of receptor-ligand interactions, we categorized the binding affinities of the antagonists for NPBWR1 and identified key residues responsible for ligand recognition by NPBWR1. Binding free energy calculations revealed that the residues Trp102(ECL1), Val113(3.29), Gln281(ECL3), and Ala274(6.58) were crucial for ligand interaction. The results of our study will be useful to understand the structure-function relationship of NPBWR1 that may assist future drug discovery initiatives.
[Show abstract][Hide abstract] ABSTRACT: Seasonal and pandemic influenza outbreaks remain a major human health problem. Inhibition of the endonuclease activity of influenza RNA-dependent RNA polymerase is attractive for the development of new agents for the treatment of influenza infection. Our earlier studies identified a series of 5- and 6-phenyl substituted 3-hydroxypyridin-2(1H)-ones that were effective inhibitors of influenza endonuclease. These agents identified as bimetal chelating ligands binding to the active site of the enzyme. In the present study, several aza analogs of these phenyl substituted 3-hydroxypyridin-2(1H)-one compounds were synthesized and evaluated for their ability to inhibit the endonuclease activity. In contrast to the 4-aza analog of 6-(4-fluorophenyl)-3-hydroxypyridin-2(1H)-one, the 5-aza analog (5-hydroxy-2-(4-fluorophenyl)pyrimidin-4(3H)-one) did exhibit significant activity as an endonuclease inhibitor. The 6-aza analog of 5-(4-fluorophenyl)-3-hydroxypyridin-2(1H)-one (6-(4-fluorophenyl)-4-hydroxypyridazin-3(2H)-one) also retained modest activity as an inhibitor. Several varied 6-phenyl-4-hydroxypyridazin-3(2H)-ones and 2-phenyl-5-hydroxypyrimidin-4(3H)-ones were synthesized and evaluated as endonuclease inhibitors. The SAR observed for these aza analogs are consistent with those previously observed with various phenyl substituted 3-hydroxypyridin-2(1H)-ones.
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