A Series of 6- and 7-Piperazinyl- and -Piperidinylmethylbenzoxazinones with Dopamine D4 Antagonist Activity:  Discovery of a Potential Atypical Antipsychotic Agent

• Published in: Journal of medicinal chemistry Vol. 42; no. 25; pp. 5181 - 5187
• Main Authors: Belliotti, Thomas R, Wustrow, David J, Brink, Wouter A, Zoski, Kim T, Shih, Yu-Hsin, Whetzel, Steven Z, Georgic, Lynn M, Corbin, Ann E, Akunne, Hyacinth C, Heffner, Thomas G, Pugsley, Thomas A, Wise, Lawrence D
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 16.12.1999; Amer Chemical Soc
• Subjects: 3,4-Dihydroxyphenylacetic Acid - metabolism; Animals; Antipsychotic Agents - chemistry; Antipsychotic Agents - pharmacology; Biological and medical sciences; Chemistry, Medicinal; CHO Cells; Corpus Striatum - drug effects; Corpus Striatum - metabolism; Cricetinae; Dopamine - biosynthesis; Dopamine - metabolism; Dopamine Antagonists - chemistry; Dopamine Antagonists - pharmacology; Dopamine D2 Receptor Antagonists; Hippocampus - drug effects; Hippocampus - metabolism; Life Sciences & Biomedicine; Magnetic Resonance Spectroscopy; Medical sciences; Neuropharmacology; Oxazines - chemistry; Oxazines - pharmacology; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Psycholeptics: tranquillizer, neuroleptic; Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; Rats; Receptors, Dopamine D4; Science & Technology; CLOZAPINE; SELECTIVE ANTAGONIST; L-745,870; LIGANDS; CLONING; CORTEX; D-4 RECEPTOR ANTAGONISTS; DRUGS; HIGH-AFFINITY; SCHIZOPHRENIA; Rat; Psychotropic; Central nervous system; Lactam; Selectivity; Structure activity relation; Chlorine Organic compounds; Piperidine derivatives; Bicyclic compound; Antipsychotic; Aromatic compound; Antagonist; Chemical synthesis; Oxygen nitrogen heterocycle; Human; D4 Dopamine receptor; Rodentia; Oral administration; In vitro; In vivo; Vertebrata; Mammalia; Mouse; Animal; Affinity; Piperazine derivatives; Brain (vertebrata)
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm990277d

As part of a program to develop dopamine D4 antagonists for the treatment of schizophrenia, we discovered a series of 6- and 7-(phenylpiperazinyl)- and -(phenylpiperidinyl)methylbenzoxazinones through mass screening of our compound library. A structure−activity relationship SAR study was carried out involving substituents on the phenyl ring, and several selective D4 antagonists were identified. The 7-substituted benzoxazinones showed more activity in neurochemical and behavioral tests than the 6-substituted series. One of the most potent and selective compounds (26) was found to have potent activity in animal tests predictive of antipsychotic activity in humans after oral administration. This paper describes the SAR of the benzoxazinone series and the preclinical characterization of 26.