Identification of a new series of non-peptidic NK₃ receptor antagonists

• Published in: Bioorganic & medicinal chemistry letters Vol. 21; no. 5; pp. 1498 - 1501
• Main Authors: Juhl, Karsten, Hansen, Tore, Kehler, Jan, Khanzhin, Nikolay A, Nørgaard, Morten B, Ruhland, Thomas, Larsen, Dorrit B, Jensen, Klaus G, Steiniger-Brach, Björn, Nielsen, Søren M, Simonsen, Klaus B
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 01.03.2011; Elsevier
• Subjects: Amides - chemical synthesis; Amides - chemistry; Amides - pharmacology; Animals; antagonists; Biological and medical sciences; brain; Carboxylic Acids - chemical synthesis; Carboxylic Acids - chemistry; Carboxylic Acids - pharmacology; Cyclopropanes - chemical synthesis; Cyclopropanes - chemistry; Cyclopropanes - pharmacology; Disease Models, Animal; Gerbillinae; gerbils; Medical sciences; Molecular Structure; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems; Peptides - chemical synthesis; Peptides - chemistry; Peptides - pharmacology; Pharmacology. Drug treatments; Psycholeptics: tranquillizer, neuroleptic; Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; Receptors, Neurokinin-3 - antagonists & inhibitors; Structure-Activity Relationship; structure-activity relationships; Cyclopropane derivatives; Neuroleptic; Psychotropic; Schizophrenia; Non peptide compound; Structure activity relation; Cyclopropane; Chlorine Organic compounds; NK3 Tachykinin receptor; Antipsychotic; Subcutaneous administration; Antagonist; Chemical synthesis; Rodentia; Benzene derivatives; In vitro; Senktide induced hypoactivity; In vivo; Vertebrata; Mammalia; Sulfonamides; Animal; Affinity; Carboxamide; Fluorine Organic compounds; Gerbil; NK
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2010.12.135

The identification and structure–activity relationships of 2-aminomethyl-1-aryl cyclopropane carboxamides as novel NK₃ receptor antagonists are reported. The compound series was optimized to give analogues with low nanomolar binding to the NK₃ receptor and brain exposure, leading to activity in vivo in the senktide-induced hypoactivity model in gerbils.