Discovery of New Heterocyclic Ring Systems as Novel and Potent V_1A Receptor Antagonists

Abstract

Autism spectrum disorder is a neurodevelopmental disease with increasing occurrence. Recent studies focus on the development of novel V1A receptor antagonists which can influence the core symptoms of autism through the AVP pathway. In this study, we describe the synthesis of new heterocyclic ring systems. These are a novel class of brain-penetrating V1A antagonists with improved metabolic stability and in vivo potency. The efficacy of the compounds was strongly influenced by the position of the chlorine atom, suggesting halogen bond formation between the ligands and the V1A receptor.

Development of a Triazolobenzodiazepine-Based PET Probe for Subtype-Selective Vasopressin 1A Receptor Imaging

“…Pharmacological data of target compound 17 was assessed for the human V1A, V1B and V2 and OT, as well as for the hERG potassium channel, the L-type calcium channel and the sodium channel ( Figure 2 ). In accordance with previous reports, 17 exhibited a high binding affinity (IC 50 = 4.7 nM and K i = 0.9 nM) towards the V1A receptor 36, 37 . Conversely, the binding affinities for related receptors, including V1B, V2 and oxytocin (OT) receptors, was >10 μM, suggesting a high compound selectivity.…”

Synthesis and Characterization of New V1A Antagonist Compounds: The Separation of Four Atropisomeric Stereoisomers

“…To explain the obtained ligand structure–V 1A activity relationship, molecular docking calculations were carried out using the refined homology models described earlier . Compounds 18 – 21 and 23 and their chloro analogues ( 6 and 29 – 30 ) were investigated in this study.…”

“…Exploring further the medicinal chemistry of this class of compounds, particularly with a view to gaining new empirical data that can facilitate a better understanding of the pertinent structure–activity relationships (SAR), compound 5 was synthesized as a first step (Table ), in which a hydroxyl group was introduced to the C-5 position of 4 . Although the homology models we had used earlier suggested a preference for apolar substituents at this position of the core, 5 was found to be a potent and selective V 1A antagonist (see the Molecular Modeling section for the resolution of this apparent contradiction). As compared to 4 , compound 5 had a smaller clog P and exhibited more favorable metabolic clearance and only slightly worse penetrability (Table ).…”

Bioisosteres of the Phenyl Ring: Recent Strategic Applications in Lead Optimization and Drug Design

“…193 An optimization program resulted in a pyridine-based subseries, from which the pyridodiazepine 109b was identified as the eutomer that demonstrated improved physicochemical properties, including enhanced solubility and HLM metabolic The low metabolic stability of the V 1A receptor antagonists 110a and 110b in RLM and MLM inspired the design of analogues using a scaffold morphing approach, in which the fused phenyl ring was replaced with an imidazole, as summarized in Table 91. 194 The new analogues 110c and 110d exhibited higher metabolic stability than their respective progenitors, although the change resulted in 10-to 140-fold reduction in intrinsic V 1A receptor inhibitory potency. Compound 110c, which exhibited a balanced overall profile, was progressed into advanced lead evaluation, which revealed it to be selective toward the V 1A receptor over both the V 2 receptor and the hERG ion channel and to demonstrate significant in vivo efficacy in an oxytocin-induced scratching test in mouse.…”

“… The low metabolic stability of the V 1A receptor antagonists 110a and 110b in RLM and MLM inspired the design of analogues using a scaffold morphing approach, in which the fused phenyl ring was replaced with an imidazole, as summarized in Table . The new analogues 110c and 110d exhibited higher metabolic stability than their respective progenitors, although the change resulted in 10- to 140-fold reduction in intrinsic V 1A receptor inhibitory potency.…”