ABSTRACT
A series of fused cyclopropyl-4,5-dihydropyridazin-3-one (3,4-diaza-bicyclo[4.1.0]hept-4-en-2-one) phenoxypiperidine analogs was designed and synthesized, leading to the identification of (1R,6S)-5-[4-(1-cyclobutyl-piperidin-4-yloxy)-phenyl]-3,4-diaza-bicyclo[4.1.0]hept-4-en-2-one (R,S-4a) as a second-generation pyridazin-3-one H3R antagonist. Compound R,S-4a was a potent H3R functional antagonist in vivo in the rat dipsogenia model, demonstrated potent wake activity in the rat EEG/EMG model, and enhanced short-term memory in the rat social recognition memory model at doses as low as 0.03-0.3 mg/kg po.
Subject(s)
Nootropic Agents/chemistry , Piperidines/chemistry , Pyridazines/chemistry , Receptors, Histamine H3/chemistry , Animals , Cognition Disorders/drug therapy , Disease Models, Animal , Dogs , Drug Evaluation, Preclinical , Drug Inverse Agonism , Half-Life , Haplorhini , Memory, Short-Term/drug effects , Nootropic Agents/pharmacokinetics , Nootropic Agents/pharmacology , Nootropic Agents/therapeutic use , Piperidines/pharmacokinetics , Piperidines/pharmacology , Piperidines/therapeutic use , Pyridazines/pharmacokinetics , Pyridazines/pharmacology , Pyridazines/therapeutic use , Rats , Receptors, Histamine H3/metabolism , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A novel class of benzocinnolinones analogs of irdabisant were designed and synthesized as histamine H3R antagonists/inverse agonists. Modifications to the pyridazinone portion of the core and linker led to the identification of molecules with excellent target potency and selectivity with improved rat pharmacokinetic properties and reduced potential hERG liabilities.
Subject(s)
Heterocyclic Compounds, 3-Ring/chemical synthesis , Histamine Agonists/chemical synthesis , Histamine H3 Antagonists/chemical synthesis , Nootropic Agents/chemical synthesis , Pyridazines/chemical synthesis , Pyrrolidines/chemical synthesis , Receptors, Histamine H3/chemistry , Animals , CHO Cells , Cell Membrane/drug effects , Cell Membrane/metabolism , Cricetinae , Dose-Response Relationship, Drug , Drug Inverse Agonism , Heterocyclic Compounds, 3-Ring/pharmacology , Histamine Agonists/pharmacology , Histamine H3 Antagonists/pharmacology , Molecular Structure , Nootropic Agents/pharmacology , Pyridazines/pharmacology , Pyrrolidines/pharmacology , Rats , Receptors, Histamine H3/metabolism , Structure-Activity RelationshipABSTRACT
Structure-activity relationships for a series of phenoxypiperidine pyridazin-3-one H(3)R antagonists/inverse agonists are disclosed. The search for compounds with improved hERG and DAT selectivity without the formation of in vivo active metabolites identified 6-[4-(1-cyclobutyl-piperidin-4-yloxy)-phenyl]-4,4-dimethyl-4,5-dihydro-2H-pyridazin-3-one 17b. Compound 17b met discovery flow criteria, demonstrated potent H(3)R functional antagonism in vivo in the rat dipsogenia model and potent wake activity in the rat EEG/EMG model at doses as low as 0.1 mg/kg ip.
Subject(s)
Histamine Antagonists/chemistry , Histamine Antagonists/pharmacology , Piperidines/chemistry , Pyridazines/chemistry , Receptors, Histamine H3 , Wakefulness/drug effects , Animals , Disease Models, Animal , Models, Molecular , Molecular Structure , Piperidines/pharmacology , Pyridazines/pharmacology , RatsABSTRACT
H(3)R structure-activity relationships for a new class of 4,5-dihydropyridazin-3-one H(3)R antagonists/inverse agonists are disclosed. Modification of the 4,5-dihydropyridazinone moiety to block in vivo metabolism identified 4,4-dimethyl-6-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-4,5-dihydro-2H-pyridazin-3-one 22 as a lead candidate demonstrating potent in vivo functional H(3)R antagonism in the rat dipsogenia model and robust wake promoting activity in the rat EEG/EMG model.
Subject(s)
Histamine Agonists/chemical synthesis , Pyridazines/chemistry , Receptors, Histamine H3/chemistry , Animals , Area Under Curve , Dose-Response Relationship, Drug , Drug Design , Electroencephalography/methods , Electromyography/methods , Histamine Agonists/pharmacology , Kinetics , Models, Chemical , Pyridazines/chemical synthesis , Pyridazines/pharmacology , Rats , Stereoisomerism , Structure-Activity Relationship , Time FactorsABSTRACT
H(3)R structure-activity relationships on a novel class of pyridazin-3-one H(3)R antagonists/inverse agonists are disclosed. Modifications of the pyridazinone core, central phenyl ring and linker led to the identification of molecules with excellent target potency, selectivity and pharmacokinetic properties. Compounds 13 and 21 displayed potent functional H(3)R antagonism in vivo in the rat dipsogenia model and demonstrated robust wake activity in the rat EEG/EMG model.
Subject(s)
Drinking/drug effects , Histamine Agonists/pharmacology , Pyridazines/pharmacology , Wakefulness/drug effects , Animals , Disease Models, Animal , Dose-Response Relationship, Drug , Histamine Agonists/chemical synthesis , Histamine Agonists/chemistry , Humans , Male , Molecular Structure , Pyridazines/chemical synthesis , Pyridazines/chemistry , Rats , Receptors, Histamine H3/metabolism , Stereoisomerism , Structure-Activity RelationshipABSTRACT
The optimization of the dihydronaphthyl[3,4-a]pyrrolo[3,4-c]carbazole-5-one R(2) and R(12) positions led to the identification of the first MLK1 and MLK3 subtype-selective inhibitors within the MLK family. Compounds 14 (CEP-5104) and 16 (CEP-6331) displayed good potency for MLK1 and MLK3 inhibition with a greater than 30- to 100-fold selectivity for related family members MLK2 and DLK. Compounds 14 and 16 were orally active in vivo in a mouse MPTP biochemical efficacy model that was comparable to the first-generation pan-MLK inhibitor 1 (CEP-1347). The MLK1 structure-activity relationships were supported by the first-reported X-ray crystal structure of MLK1 bound with 16.