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

• Published in: Bioorganic & medicinal chemistry letters Vol. 26; no. 16; pp. 3896 - 3904
• Main Authors: Szántó, Gábor, Makó, Attila, Bata, Imre, Farkas, Bence, Kolok, Sándor, Vastag, Mónika, Cselenyák, Attila
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 15.08.2016; Elsevier
• Subjects: Adenosine Triphosphate - metabolism; Airway hyperractivity; ATP; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Chirality; Drug Evaluation, Preclinical; Heterocyclic Compounds - chemistry; Heterocyclic Compounds, 3-Ring - chemical synthesis; Heterocyclic Compounds, 3-Ring - chemistry; HTS campaign; Humans; Inhibitory Concentration 50; Ion channel; Life Sciences & Biomedicine; Mesylates - chemical synthesis; Mesylates - chemistry; Microsomes - metabolism; New binding site; P2X3 antagonist; Pharmacology & Pharmacy; Physical Sciences; Protein Binding; Purinergic P2X Receptor Antagonists - chemical synthesis; Purinergic P2X Receptor Antagonists - chemistry; Purinergic P2X Receptor Antagonists - metabolism; Purinergic receptor; Receptors, Purinergic P2X3 - chemistry; Receptors, Purinergic P2X3 - metabolism; Science & Technology; Structure-Activity Relationship; Purinergic receptor; Chirality; Airway hyperractivity; P2X3 antagonist; New binding site; Ion channel; ATP; HTS campaign; CACO-2
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2016.07.009

[Display omitted] 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.