New P2X3 receptor antagonists. Part 1: Discovery and optimization of tricyclic compounds.

Authors :: Szántó G
Makó A
Bata I
Farkas B
Kolok S
Vastag M
Cselenyák A
Source :: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2016 Aug 15; Vol. 26 (16), pp. 3896-904. Date of Electronic Publication: 2016 Jul 05.
Publication Year :: 2016
Abstract: Purinergic P2X3 receptors are trimeric ligand-gated ion channels whose antagonism is an appealing yet challenging and not fully validated drug development idea. With the aim of identification of an orally active, potent human P2X3 receptor antagonist compound that can penetrate the central nervous system, the compound collection of Gedeon Richter was screened. A hit series of tricyclic compounds was subjected to a rapid, two-step optimization process focusing on increasing potency, improving metabolic stability and CNS penetrability. Attempts resulted in compound 65, a potential tool compound for testing P2X3 inhibitory effects in vivo.<br /> (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Subjects :: Adenosine Triphosphate metabolism
Drug Evaluation, Preclinical
Heterocyclic Compounds, 3-Ring chemistry
Humans
Inhibitory Concentration 50
Mesylates chemistry
Microsomes metabolism
Protein Binding
Purinergic P2X Receptor Antagonists chemical synthesis
Purinergic P2X Receptor Antagonists metabolism
Receptors, Purinergic P2X3 chemistry
Structure-Activity Relationship
Heterocyclic Compounds chemistry
Heterocyclic Compounds, 3-Ring chemical synthesis
Mesylates chemical synthesis
Purinergic P2X Receptor Antagonists chemistry
Receptors, Purinergic P2X3 metabolism

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