RESUMO
CEP-32215 is a new, potent, selective, and orally bioavailable inverse agonist of the histamine H3 receptor (H3R) with drug-like properties. High affinity in human (hH3R Ki = 2.0 ± 0.2 nM) and rat (rH3R Ki = 3.6 ± 0.7 nM) H3R radioligand binding assays was demonstrated. Potent functional antagonism (Kb = 0.3 ± 0.1 nM) and inverse agonism (EC50 = 0.6 ± 0.2 nM) were demonstrated in [(35)S]guanosine 5(')-O-(γ-thio)-triphosphate binding assays. Oral bioavailability and dose-related exposure was consistent among rat, dog, and monkey. After oral dosing, occupancy of H3R by CEP-32215 was estimated by the inhibition of ex vivo binding in rat cortical slices (ED50 = 0.1 mg/kg p.o.). Functional antagonism in brain was demonstrated by the inhibition of R-α-methylhistamine-induced drinking in the rat dipsogenia model (ED50 = 0.92 mg/kg). CEP-32215 significantly increased wake duration in the rat EEG model at 3-30 mg/kg p.o. Increased motor activity, sleep rebound or undesirable events (such as spike wave or seizure activity) was not observed following doses up to 100 mg/kg p.o., indicating an acceptable therapeutic index. CEP-32215 may have potential utility in the treatment of a variety of sleep disorders. This article is part of the Special Issue entitled 'Histamine Receptors'.
Assuntos
Agonismo Inverso de Drogas , Antagonistas dos Receptores Histamínicos H3/farmacologia , Piperidinas/farmacologia , Pirazinas/farmacologia , Compostos de Espiro/farmacologia , Vigília/efeitos dos fármacos , Administração Oral , Animais , Disponibilidade Biológica , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Cães , Ingestão de Líquidos/efeitos dos fármacos , Ingestão de Líquidos/fisiologia , Avaliação Pré-Clínica de Medicamentos , Agonistas dos Receptores Histamínicos/farmacologia , Antagonistas dos Receptores Histamínicos H3/farmacocinética , Humanos , Macaca fascicularis , Masculino , Metilistaminas/farmacologia , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Piperidinas/farmacocinética , Pirazinas/farmacocinética , Ratos Sprague-Dawley , Receptores Histamínicos H3/metabolismo , Sono/efeitos dos fármacos , Sono/fisiologia , Compostos de Espiro/farmacocinética , Vigília/fisiologiaRESUMO
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.
Assuntos
Agonismo Inverso de Drogas , Antagonistas dos Receptores Histamínicos/química , Antagonistas dos Receptores Histamínicos/farmacologia , Piridazinas/química , Piridazinas/farmacologia , Pirrolidinas/química , Pirrolidinas/farmacologia , Receptores Histamínicos H3/metabolismo , Vigília/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Desenho de Fármacos , Antagonistas dos Receptores Histamínicos/farmacocinética , Humanos , Piridazinas/farmacocinética , Pirrolidinas/farmacocinética , Ratos , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Nootrópicos/química , Piperidinas/química , Piridazinas/química , Receptores Histamínicos H3/química , Animais , Transtornos Cognitivos/tratamento farmacológico , Modelos Animais de Doenças , Cães , Avaliação Pré-Clínica de Medicamentos , Agonismo Inverso de Drogas , Meia-Vida , Haplorrinos , Memória de Curto Prazo/efeitos dos fármacos , Nootrópicos/farmacocinética , Nootrópicos/farmacologia , Nootrópicos/uso terapêutico , Piperidinas/farmacocinética , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Piridazinas/farmacocinética , Piridazinas/farmacologia , Piridazinas/uso terapêutico , Ratos , Receptores Histamínicos H3/metabolismo , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Utilizing atypical wake-promoting agent modafinil (inactive in both rH(3) and hH(3) binding assays) as a launching pad, a series of sulfinyl- and sulfone-derived H(3) receptor inverse agonists were developed. Brain-permeable compound 27, a potent member of the series displayed excellent selectivity against related family members (H(1), H(2), and H(4) receptors).
Assuntos
Compostos Benzidrílicos/química , Pirrolidinas/química , Receptores Histamínicos H3/química , Sulfonas/química , Administração Oral , Animais , Compostos Benzidrílicos/agonistas , Compostos Benzidrílicos/farmacocinética , Estimulantes do Sistema Nervoso Central/agonistas , Estimulantes do Sistema Nervoso Central/química , Estimulantes do Sistema Nervoso Central/farmacocinética , Agonismo Inverso de Drogas , Meia-Vida , Cinética , Modafinila , Ligação Proteica , Pirrolidinas/agonistas , Pirrolidinas/farmacocinética , Ratos , Receptores Histamínicos H3/metabolismo , Relação Estrutura-Atividade , Sulfonas/agonistas , Sulfonas/farmacocinética , Vigília/efeitos dos fármacosRESUMO
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.
Assuntos
Antagonistas dos Receptores Histamínicos/síntese química , Antagonistas dos Receptores Histamínicos/farmacologia , Propilaminas/farmacologia , Piridazinas/farmacologia , Receptores Histamínicos H3/metabolismo , Animais , Antagonistas dos Receptores Histamínicos/química , Humanos , Masculino , Dados de Sequência Molecular , Estrutura Molecular , Propilaminas/síntese química , Propilaminas/química , Piridazinas/síntese química , Piridazinas/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Compostos Heterocíclicos com 3 Anéis/síntese química , Agonistas dos Receptores Histamínicos/síntese química , Antagonistas dos Receptores Histamínicos H3/síntese química , Nootrópicos/síntese química , Piridazinas/síntese química , Pirrolidinas/síntese química , Receptores Histamínicos H3/química , Animais , Células CHO , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Cricetinae , Relação Dose-Resposta a Droga , Agonismo Inverso de Drogas , Compostos Heterocíclicos com 3 Anéis/farmacologia , Agonistas dos Receptores Histamínicos/farmacologia , Antagonistas dos Receptores Histamínicos H3/farmacologia , Estrutura Molecular , Nootrópicos/farmacologia , Piridazinas/farmacologia , Pirrolidinas/farmacologia , Ratos , Receptores Histamínicos H3/metabolismo , Relação Estrutura-AtividadeRESUMO
Optimization of a series of aminomethyl ketone diamine H(3)R antagonists to reduce the brain exposure by lowering the pKa, led to molecules with improved pharmacokinetic properties. Compounds 9, 19, and 25 had high affinity for human H(3)R and demonstrated in vivo H(3)R functional activity in the rat dipsogenia model. Compound 9 displayed modest wake-promoting activity in the rat EEG/EMG model.
Assuntos
Agonismo Inverso de Drogas , Agonistas dos Receptores Histamínicos , Cetonas/química , Vigília/efeitos dos fármacos , 1-Propanol/química , 1-Propanol/farmacologia , Animais , Agonistas dos Receptores Histamínicos/química , Agonistas dos Receptores Histamínicos/farmacologia , Humanos , Cetonas/farmacologia , Metilaminas/química , Metilaminas/farmacologia , Fenóis/química , Fenóis/farmacologia , Pirrolidinas/química , Pirrolidinas/farmacologia , Ratos , Transtornos do Sono do Ritmo Circadiano/tratamento farmacológicoRESUMO
Structure-activity relationship on a novel ketone class of H(3)R antagonists/inverse agonists is disclosed. Compound 4 showed excellent target potency, selectivity and brain penetration. Evaluation of antagonist 4 in the rat EEG/EMG model demonstrated robust wake activity thereby establishing preclinical proof of concept.
Assuntos
Agonistas dos Receptores Histamínicos/farmacologia , Cetonas/química , Morfolinas/química , Receptores Histamínicos H3 , Vigília/efeitos dos fármacos , Animais , Eletroencefalografia , Agonistas dos Receptores Histamínicos/química , Humanos , Cetonas/farmacologia , Masculino , Estrutura Molecular , Morfolinas/farmacologia , Ratos , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Antagonistas dos Receptores Histamínicos/química , Antagonistas dos Receptores Histamínicos/farmacologia , Piperidinas/química , Piridazinas/química , Receptores Histamínicos H3 , Vigília/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Modelos Moleculares , Estrutura Molecular , Piperidinas/farmacologia , Piridazinas/farmacologia , RatosRESUMO
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.
Assuntos
Benzopiranos/síntese química , Antagonistas dos Receptores Histamínicos/síntese química , Piperidinas/síntese química , Receptores Histamínicos H3/metabolismo , Compostos de Espiro/síntese química , Administração Oral , Animais , Benzopiranos/farmacocinética , Benzopiranos/farmacologia , Sistema Enzimático do Citocromo P-450/metabolismo , Antagonistas dos Receptores Histamínicos/farmacocinética , Antagonistas dos Receptores Histamínicos/farmacologia , Humanos , Injeções Intravenosas , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Piperidinas/farmacocinética , Piperidinas/farmacologia , Ratos , Compostos de Espiro/farmacocinética , Compostos de Espiro/farmacologia , Relação Estrutura-AtividadeRESUMO
Optimization of the R(2) and R(6) positions of (5-{4-[3-(R)-2-methylpyrrolin-1-yl-propoxy]phenyl}-2H-pyridazin-3-one) 2a with constrained phenoxypiperidines led to the identification of 5-[4-(cyclobutyl-piperidin-4-yloxy)-phenyl]-6-methyl-2H-pyridazin-3-one 8b as a potent, selective histamine H(3) receptor antagonist with favorable pharmacokinetic properties. Compound 8b had an excellent safety genotoxocity profile for a CNS-active compound in the Ames and micronucleus tests, also displayed potent H(3)R antagonist activity in the brain in the rat dipsogenia model and robust wake activity in the rat EEG/EMG model.
Assuntos
Piperidinas/farmacologia , Piridazinas/farmacologia , Receptores Histamínicos H3/química , Animais , Humanos , Estrutura Molecular , Piperidinas/síntese química , Piperidinas/química , Piridazinas/síntese química , Piridazinas/química , Ratos , Receptores Histamínicos H3/metabolismo , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Agonistas dos Receptores Histamínicos/síntese química , Piridazinas/química , Receptores Histamínicos H3/química , Animais , Área Sob a Curva , Relação Dose-Resposta a Droga , Desenho de Fármacos , Eletroencefalografia/métodos , Eletromiografia/métodos , Agonistas dos Receptores Histamínicos/farmacologia , Cinética , Modelos Químicos , Piridazinas/síntese química , Piridazinas/farmacologia , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Fatores de TempoRESUMO
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.
Assuntos
Antagonistas dos Receptores Histamínicos/química , Piperidinas/química , Receptores Histamínicos H3/química , Compostos de Espiro/síntese química , Animais , Química Farmacêutica/métodos , Desenho de Fármacos , Interações Medicamentosas , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Humanos , Concentração Inibidora 50 , Cinética , Fígado/metabolismo , Camundongos , Modelos Químicos , Ratos , Compostos de Espiro/farmacologia , Relação Estrutura-AtividadeRESUMO
Previous studies have shown that (5-{4-[3-(R)-2-methylpyrrolin-1-yl-propoxy]phenyl}-2H-pyridazin-3-one) 2 had high affinity for both the human (hH(3)R K(i) = 2.8 nM) and rat H(3)Rs (rH(3)R K(i) = 8.5 nM) but displayed low oral bioavailability in the rat. Optimization of the 5-pyridazin-3-one R(2) and R(6) positions to improve the pharmacokinetic properties over 2 led to the identification of 5-{4-[3-(R)-2-methylpyrrolidin-1-yl)propoxy]phenyl}-2-pyridin-2-yl-2H-pyridazin-3-one 29. Compound 29 displayed high affinity for both human and rat H(3)Rs (hH(3)R K(i) = 1.7 nM, rH(3)R K(i) = 3.7 nM) with a greater than 1000-fold selectivity over the other histamine receptor subtypes and favorable pharmacokinetic properties across species (F = 78% rat, 92% dog, 96% monkey). It showed low binding to human plasma proteins, weakly inhibited cytochrome P450 isoforms, and displayed an excellent safety profile for a CNS-active compound. 29 displayed potent H(3)R antagonist activity in the brain in a rat dipsogenia model and demonstrated enhancement of cognitive function in a rat social recognition model at low doses. However, the development of compound 29 was discontinued because of genotoxicity.
Assuntos
Nootrópicos/síntese química , Propilaminas/síntese química , Piridazinas/síntese química , Receptores Histamínicos H3/metabolismo , Animais , Células CHO , Cricetinae , Cricetulus , Cães , Agonismo Inverso de Drogas , Agonistas dos Receptores Histamínicos/síntese química , Agonistas dos Receptores Histamínicos/farmacocinética , Agonistas dos Receptores Histamínicos/farmacologia , Antagonistas dos Receptores Histamínicos H3/síntese química , Antagonistas dos Receptores Histamínicos H3/farmacocinética , Antagonistas dos Receptores Histamínicos H3/farmacologia , Humanos , Macaca fascicularis , Masculino , Memória de Curto Prazo/efeitos dos fármacos , Testes de Mutagenicidade , Nootrópicos/farmacocinética , Nootrópicos/farmacologia , Propilaminas/farmacocinética , Propilaminas/farmacologia , Piridazinas/farmacocinética , Piridazinas/farmacologia , Ensaio Radioligante , Ratos , Ratos Long-Evans , Ratos Sprague-Dawley , Reconhecimento Psicológico/efeitos dos fármacos , Estereoisomerismo , Relação Estrutura-Atividade , Sede/efeitos dos fármacos , Distribuição TecidualRESUMO
CEP-26401 [irdabisant; 6-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-2H-pyridazin-3-one HCl] is a novel, potent histamine H3 receptor (H3R) antagonist/inverse agonist with drug-like properties. High affinity of CEP-26401 for H3R was demonstrated in radioligand binding displacement assays in rat brain membranes (K(i) = 2.7 ± 0.3 nM) and recombinant rat and human H3R-expressing systems (K(i) = 7.2 ± 0.4 and 2.0 ± 1.0 nM, respectively). CEP-26401 displayed potent antagonist and inverse agonist activities in [³5S]guanosine 5'-O-(γ-thio)triphosphate binding assays. After oral dosing of CEP-26401, occupancy of H3R was estimated by the inhibition of ex vivo binding in rat cortical slices (OCC50 = 0.1 ± 0.003 mg/kg), and antagonism of the H3R agonist R-α-methylhistamine- induced drinking response in the rat dipsogenia model was demonstrated in a similar dose range (ED50 = 0.06 mg/kg). CEP-26401 improved performance in the rat social recognition model of short-term memory at doses of 0.01 to 0.1 mg/kg p.o. and was wake-promoting at 3 to 30 mg/kg p.o. In DBA/2NCrl mice, CEP-26401 at 10 and 30 mg/kg i.p. increased prepulse inhibition (PPI), whereas the antipsychotic risperidone was effective at 0.3 and 1 mg/kg i.p. Coadministration of CEP-26401 and risperidone at subefficacious doses (3 and 0.1 mg/kg i.p., respectively) increased PPI. These results demonstrate potent behavioral effects of CEP-26401 in rodent models and suggest that this novel H3R antagonist may have therapeutic utility in the treatment of cognitive and attentional disorders. CEP-26401 may also have therapeutic utility in treating schizophrenia or as adjunctive therapy to approved antipsychotics.
Assuntos
Cognição/efeitos dos fármacos , Antagonistas dos Receptores Histamínicos H3/farmacologia , Nootrópicos , Piridazinas/farmacologia , Pirrolidinas/farmacologia , Vigília/efeitos dos fármacos , Animais , Autorradiografia , Comportamento Animal/efeitos dos fármacos , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , DNA Complementar/biossíntese , DNA Complementar/genética , Relação Dose-Resposta a Droga , Ingestão de Líquidos/efeitos dos fármacos , Eletroencefalografia/efeitos dos fármacos , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Masculino , Memória de Curto Prazo/efeitos dos fármacos , Ensaio Radioligante , Ratos , Ratos Long-Evans , Ratos Sprague-Dawley , Reconhecimento Psicológico/efeitos dos fármacos , Reflexo de Sobressalto/efeitos dos fármacos , Sono/efeitos dos fármacos , Comportamento SocialRESUMO
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.
Assuntos
Antagonistas dos Receptores Histamínicos H3/síntese química , Antagonistas dos Receptores Histamínicos H3/farmacologia , Piridazinas/síntese química , Piridazinas/farmacologia , Pirrolidinas/síntese química , Pirrolidinas/farmacologia , Animais , Modelos Animais de Doenças , Antagonistas dos Receptores Histamínicos H3/química , Humanos , Estrutura Molecular , Ligação Proteica/efeitos dos fármacos , Piridazinas/química , Pirrolidinas/química , Ratos , Relação Estrutura-AtividadeRESUMO
Three series of novel 4,5-fused pyridazinones were synthesized as histamine H(3) receptor antagonists. The 2,5,6,7-tetrahydrocyclopenta[d]pyridazin-1-one 5q and 5,6,7,8-tetrahydro-2H-phthalazin-1-one 5u displayed high affinity at both rat and human H(3) receptors, and showed potent antagonist and full inverse agonist activity in functional assays.
Assuntos
Antagonistas dos Receptores Histamínicos H3/química , Antagonistas dos Receptores Histamínicos H3/farmacologia , Piridazinas/química , Piridazinas/farmacologia , Receptores Histamínicos H3/metabolismo , Animais , Antagonistas dos Receptores Histamínicos H3/farmacocinética , Humanos , Piridazinas/farmacocinética , Ratos , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Antagonistas dos Receptores Histamínicos H3/síntese química , Antagonistas dos Receptores Histamínicos H3/farmacologia , Administração Oral , Animais , Disponibilidade Biológica , Eletroencefalografia , Eletromiografia , Antagonistas dos Receptores Histamínicos H3/farmacocinética , Humanos , Ratos , Relação Estrutura-AtividadeRESUMO
Pyridazinone 1 was recently reported as a potent H(3)R antagonist with good drug-like properties and in vivo activity. A series of constrained amine analogs of 1 was synthesized to identify compounds with improved pharmacokinetic profiles. From these efforts, a new class of (S)-2-pyrrolidin-1-ylmethyl-1-pyrrolidinyl amides was identified.
Assuntos
Aminas/química , Antagonistas dos Receptores Histamínicos H3/farmacologia , Piridazinas/farmacologia , Animais , Relação Dose-Resposta a Droga , Antagonistas dos Receptores Histamínicos H3/síntese química , Antagonistas dos Receptores Histamínicos H3/química , Humanos , Estrutura Molecular , Piridazinas/síntese química , Piridazinas/química , Ratos , Receptores Histamínicos H3/metabolismo , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
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.