ABSTRACT
Herein we describe a series of tetrahydrobenzotriazoles as novel, potent metabotropic glutamate receptor subtype 5 (mGlu5) positive allosteric modulators (PAMs). Exploration of the SAR surrounding the tetrahydrobenzotriazole core ultimately led to the identification of 29 as a potent mGlu5 PAM with a low maximal glutamate potency fold shift, acceptable in vitro DMPK parameters and in vivo PK profile and efficacy in the rat novel object recognition (NOR) assay. As a result 29 was identified as a suitable compound for progression to in vivo safety evaluation.
Subject(s)
Antipsychotic Agents/chemistry , Receptor, Metabotropic Glutamate 5/antagonists & inhibitors , Triazoles/chemistry , Allosteric Regulation/drug effects , Animals , Antipsychotic Agents/metabolism , Antipsychotic Agents/pharmacology , Astrocytes/cytology , Astrocytes/drug effects , Astrocytes/metabolism , Cognition/drug effects , Disease Models, Animal , Drug Evaluation, Preclinical , Half-Life , Humans , Microsomes/metabolism , Rats , Receptor, Metabotropic Glutamate 5/metabolism , Structure-Activity Relationship , Triazoles/metabolism , Triazoles/pharmacologyABSTRACT
The identification of a highly selective D(2) partial agonist, D(3) antagonist tool molecule which demonstrates high levels of brain exposure and selectivity against an extensive range of dopamine, serotonin, adrenergic, histamine, and muscarinic receptors is described.
Subject(s)
Brain/drug effects , Dopamine Agonists/pharmacology , Dopamine Antagonists/pharmacology , Receptors, Dopamine D2/agonists , Receptors, Dopamine D3/antagonists & inhibitors , Animals , Brain/metabolismSubject(s)
Benzene Derivatives/chemistry , Carbohydrates/chemical synthesis , Mannose/chemistry , Benzene Derivatives/chemical synthesis , Carbohydrates/chemistry , Crystallography, X-Ray , Cyclohexanones/chemistry , Cyclohexenes/chemistry , Hydrocarbons, Aromatic/chemistry , Molecular Structure , Oxazoles/chemistry , StereoisomerismABSTRACT
A rational structure-activity relationship study around compound (1) is reported. The lead optimisation programme led to the identification of sulfonamide (25), a molecule combining dopamine D2/D3 receptor antagonism with serotonin 5-HT2A, 5-HT2C, 5-HT6 receptor antagonism for an effective treatment of schizophrenia. Compound (25) was shown to possess the required in vivo activity with no EPS liability.
Subject(s)
Antipsychotic Agents/chemical synthesis , Antipsychotic Agents/pharmacology , Alkylation , Cytochrome P-450 Enzyme System/chemistry , Cytochrome P-450 Enzyme System/metabolism , Dopamine Antagonists/chemical synthesis , Dopamine Antagonists/pharmacology , Dopamine D2 Receptor Antagonists , Drug Design , Humans , Receptor, Serotonin, 5-HT2A/drug effects , Receptor, Serotonin, 5-HT2C/drug effects , Receptors, Dopamine D3/antagonists & inhibitors , Receptors, Serotonin/drug effects , Recombinant Proteins/drug effects , Serotonin Antagonists/chemical synthesis , Serotonin Antagonists/pharmacology , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/pharmacologyABSTRACT
[reaction: see text] Aryl epoxyazides undergo efficient electron-deficient reaction cascades mediated by Lewis acids, leading to regiospecific amination of the aromatic ring.
