title: New P2X3 receptor antagonists. Part 1: Discovery and optimization of tricyclic compounds.
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.
authors.affiliation: Gedeon Richter Plc, Budapest 10, PO Box 27, H-1475, Hungary.
authors.forename: Gábor
authors.initials: G
authors.lastname: Szántó
authors.affiliation: Gedeon Richter Plc, Budapest 10, PO Box 27, H-1475, Hungary.
authors.forename: Attila
authors.initials: A
authors.lastname: Makó
authors.affiliation: Gedeon Richter Plc, Budapest 10, PO Box 27, H-1475, Hungary.
authors.forename: Imre
authors.initials: I
authors.lastname: Bata
authors.affiliation: Gedeon Richter Plc, Budapest 10, PO Box 27, H-1475, Hungary.
authors.forename: Bence
authors.initials: B
authors.lastname: Farkas
authors.affiliation: Gedeon Richter Plc, Budapest 10, PO Box 27, H-1475, Hungary.
authors.forename: Sándor
authors.initials: S
authors.lastname: Kolok
authors.affiliation: Gedeon Richter Plc, Budapest 10, PO Box 27, H-1475, Hungary.
authors.forename: Mónika
authors.initials: M
authors.lastname: Vastag
authors.affiliation: Gedeon Richter Plc, Budapest 10, PO Box 27, H-1475, Hungary.
authors.forename: Attila
authors.initials: A
authors.lastname: Cselenyák
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D006571:Heterocyclic Compounds / Q000737:chemistry*; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis* / Q000737:chemistry; D006801:Humans; D020128:Inhibitory Concentration 50; D008698:Mesylates / Q000138:chemical synthesis* / Q000737:chemistry; D008861:Microsomes / Q000378:metabolism; D011485:Protein Binding; D058920:Purinergic P2X Receptor Antagonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D058477:Receptors, Purinergic P2X3 / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D006571:Heterocyclic Compounds; D006575:Heterocyclic Compounds, 3-Ring; D008698:Mesylates; D058920:Purinergic P2X Receptor Antagonists; D058477:Receptors, Purinergic P2X3; D000255:Adenosine Triphosphate
keywords: ATP; Airway hyperractivity; Chirality; HTS campaign; Ion channel; New binding site; P2X3 antagonist; Purinergic receptor