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 1'-cyclobutyl-6-(4-piperidyloxy)spiro[benzopyran-2,4'-piperidine] derivatives with low nanomolar affinity for the human and rat histamine-3 receptors (H(3)Rs) are described. The spirobenzopyran piperidine ether analogs demonstrated excellent H(3)R affinity and selectivity against histamine receptor subtypes (H(1)R, H(2)R, and H(4)R), were stable in liver microsomes, and had selectivity against CYP P450 enzymes. Compounds 10, 13, 15, and 16 demonstrated high H(3)R affinity, in vitro liver microsomal stability, selectivity against CYP isoforms, moreover, these ether analogs exhibited acceptable iv pharmacokinetic (PK) properties but had poor oral exposure in rat.
Subject(s)
Benzopyrans/chemical synthesis , Histamine Antagonists/chemical synthesis , Piperidines/chemical synthesis , Receptors, Histamine H3/metabolism , Spiro Compounds/chemical synthesis , Administration, Oral , Animals , Benzopyrans/pharmacokinetics , Benzopyrans/pharmacology , Cytochrome P-450 Enzyme System/metabolism , Histamine Antagonists/pharmacokinetics , Histamine Antagonists/pharmacology , Humans , Injections, Intravenous , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Piperidines/pharmacokinetics , Piperidines/pharmacology , Rats , Spiro Compounds/pharmacokinetics , Spiro Compounds/pharmacology , Structure-Activity RelationshipABSTRACT
A novel class of 4-alkoxy-[1'-cyclobutyl-spiro(3,4-dihydrobenzopyran-2,4'-piperidine)] analogues were designed and synthesized as H(3)R antagonists. Structure-activity relationship identified sulfone 27 with excellent H(3)R affinities in both humans and rats, and acceptable pharmacokinetic properties. Further, compound 28 achieved single digit nanomolar H(3)R affinities in both species with minimum hERG activity.
Subject(s)
Histamine Antagonists/chemistry , Piperidines/chemistry , Receptors, Histamine H3/chemistry , Spiro Compounds/chemical synthesis , Animals , Chemistry, Pharmaceutical/methods , Drug Design , Drug Interactions , ERG1 Potassium Channel , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , Humans , Inhibitory Concentration 50 , Kinetics , Liver/metabolism , Mice , Models, Chemical , Rats , Spiro Compounds/pharmacology , 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
A novel series of 4-pyridazin-3-one and 5-pyridazin-3-one analogues were designed and synthesized as H(3)R antagonists. Structure-activity relationship revealed the 5-pyridazin-3-ones 8a and S-methyl 8b had excellent human and rat H(3)R affinities, and acceptable pharmacokinetic properties. In vivo evaluation of 8a showed potent activity in the rat dipsogenia model and robust wake-promoting activity in the rat EEG/EMG model.
Subject(s)
Histamine Antagonists/chemical synthesis , Histamine Antagonists/pharmacology , Propylamines/pharmacology , Pyridazines/pharmacology , Receptors, Histamine H3/metabolism , Animals , Histamine Antagonists/chemistry , Humans , Male , Molecular Sequence Data , Molecular Structure , Propylamines/chemical synthesis , Propylamines/chemistry , Pyridazines/chemical synthesis , Pyridazines/chemistry , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
6-{4-[3-(R)-2-Methylpyrrolidin-1-yl)propoxy]-phenyl}-2H-pyridazin-3-one 6 (Irdabisant; CEP-26401) was recently reported as a potent H(3)R antagonist with excellent drug-like properties and in vivo activity that advanced into clinical evaluation. A series of pyridone analogs of 6 was synthesized and evaluated as H(3)R antagonists. Structure-activity relationships revealed that the 5-pyridone regiomer was optimal for H(3)R affinity. N-Methyl 9b showed excellent H(3)R affinity, acceptable pharmacokinetics and pharmaceutical properties. In vivo evaluation of 9b showed potent activity in the rat dipsogenia model and robust wake-promoting activity in the rat EEG model.
Subject(s)
Histamine H3 Antagonists/chemical synthesis , Histamine H3 Antagonists/pharmacology , Pyridazines/chemical synthesis , Pyridazines/pharmacology , Pyrrolidines/chemical synthesis , Pyrrolidines/pharmacology , Animals , Disease Models, Animal , Histamine H3 Antagonists/chemistry , Humans , Molecular Structure , Protein Binding/drug effects , Pyridazines/chemistry , Pyrrolidines/chemistry , Rats , Structure-Activity RelationshipABSTRACT
A novel series of 3,4-diaza-bicyclo[4.1.0]hept-4-en-2-ones were designed and synthesized as H3R analogs of irdabisant 6. Separation of the isomers, assignment of the stereochemistry by crystallography, and detailed profiling of diastereomers 25 and 26 led to the identification of (1R,6S)-5-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)propoxy]phenyl}-3,4-diaza-bicyclo[4.1.0]hept-4-en-2-one 25 as a potential second generation H3R candidate. Diastereomer 25 had high H3R binding affinity, excellent selectivity, displayed potent H3R functional antagonism and robust wake-promoting activity in vivo, and showed acceptable pharmacokinetic and pharmaceutical profiles for potential further development.