ABSTRACT
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
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
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 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
A series of pyridazinone-phenethylamine derivatives with moderate to low nanomolar affinity for rat and human H(3)R are described. These analogs exhibited excellent selectivity and metabolic stability, with acceptable rat pharmacokinetic properties. In vivo, 7 and 11 demonstrated potent H(3)R functional antagonism in the rat dipsogenia model and robust wake-promoting activity in the rat electroencephalogram/electromyography (EEG/EMG) model.
Subject(s)
Histamine H3 Antagonists/chemical synthesis , Histamine H3 Antagonists/pharmacology , Administration, Oral , Animals , Biological Availability , Electroencephalography , Electromyography , Histamine H3 Antagonists/pharmacokinetics , Humans , Rats , Structure-Activity RelationshipABSTRACT
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.
