RESUMO
A series of α7 nicotinic acetylcholine receptor full-agonists with a 1,3,4-oxadiazol-2-amine core has been discovered. Systematic exploration of the structure-activity relationships for both α7 potency and selectivity with respect to interaction with the hERG channel are described. Further profiling led to the identification of compound 22, a potent full agonist showing efficacy in the novel object recognition model of cognition enhancement.
Assuntos
Cognição/efeitos dos fármacos , Agonistas Nicotínicos/farmacologia , Receptores Nicotínicos/efeitos dos fármacos , Animais , Cães , Agonistas Nicotínicos/química , Receptor Nicotínico de Acetilcolina alfa7RESUMO
A series of α7 nicotinic acetylcholine receptor full agonists with a 1,3,4-oxadiazol-2-amine core has been discovered. Early lead 1 was found to have a limited therapeutic index with respect to its potential for cardiovascular side effects. Further optimisation of this series led to the identification of 22 a potent full agonist showing efficacy at a dose of 0.1mg/kg in the novel object recognition model of cognition enhancement. Comparison of 1 with 22 demonstrated the latter to have an improved oral pharmacokinetic profile and cardiovascular therapeutic index.
Assuntos
Cognição/efeitos dos fármacos , Agonistas Nicotínicos/farmacologia , Receptores Nicotínicos/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Coelhos , Receptores Nicotínicos/química , Receptor Nicotínico de Acetilcolina alfa7RESUMO
We describe the discovery and optimization of a novel series of benzofuran EP(1) antagonists, leading to the identification of 26d, a novel nonacidic EP(1) antagonist which demonstrated efficacy in preclinical models of chronic inflammatory pain.
Assuntos
Anti-Inflamatórios não Esteroides/química , Benzofuranos/química , Receptores de Prostaglandina E Subtipo EP1/antagonistas & inibidores , Animais , Anti-Inflamatórios não Esteroides/farmacocinética , Anti-Inflamatórios não Esteroides/uso terapêutico , Benzofuranos/farmacocinética , Benzofuranos/uso terapêutico , Linhagem Celular , Modelos Animais de Doenças , Cães , Avaliação Pré-Clínica de Medicamentos , Dor/tratamento farmacológico , Ratos , Receptores de Prostaglandina E Subtipo EP1/metabolismo , Relação Estrutura-AtividadeRESUMO
Herein we describe the medicinal chemistry programme to identify a potential back-up compound to the EP(1) receptor antagonist GW848687X. This work started with the lipophilic 1,2-biaryl benzene derivative 4 which displayed molecular weight of 414.9g/mol and poor in vivo metabolic stability in the rat and resulted in the identification of compound 7i (GSK345931A) which demonstrated good metabolic stability in the rat and lower molecular weight (381.9g/mol). In addition, 7i (GSK345931A) showed measurable CNS penetration in the mouse and rat and potent analgesic efficacy in acute and sub-chronic models of inflammatory pain.
Assuntos
Inflamação/tratamento farmacológico , Dor/tratamento farmacológico , Piridinas/farmacologia , Receptores de Prostaglandina E/antagonistas & inibidores , Animais , Avaliação Pré-Clínica de Medicamentos , Piridinas/química , Piridinas/uso terapêutico , Ratos , Receptores de Prostaglandina E Subtipo EP1 , Relação Estrutura-AtividadeRESUMO
We describe the medicinal chemistry programme that led to the identification of the EP(1) receptor antagonist GSK269984A (8h). GSK269984A was designed to overcome development issues encountered with previous EP(1) antagonists such as GW848687X and was found to display excellent activity in preclinical models of inflammatory pain. However, upon cross species pharmacokinetic profiling, GSK269984A was predicted to have suboptimal human pharmacokinetic and was thus progressed to a human microdose study.
Assuntos
Analgésicos/síntese química , Química Farmacêutica/métodos , Inflamação/tratamento farmacológico , Ácidos Nicotínicos/síntese química , Piridinas/síntese química , Receptores de Prostaglandina E/antagonistas & inibidores , Analgésicos/farmacologia , Animais , Sistema Nervoso Central/efeitos dos fármacos , Desenho de Fármacos , Humanos , Concentração de Íons de Hidrogênio , Concentração Inibidora 50 , Modelos Químicos , Ácidos Nicotínicos/farmacologia , Piridinas/farmacologia , Ratos , Relação Estrutura-AtividadeRESUMO
We describe the SAR, in terms of heterocyclic replacements, for a series of pyrazole EP(1) receptor antagonists. This study led to the identification of several aromatic heterocyclic replacements for the pyrazole in the original compound. Investigation of replacements for the methylene linker uncovered disparate SAR in the thiazole and pyridine series.
Assuntos
Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacologia , Receptores de Prostaglandina E/antagonistas & inibidores , Modelos Moleculares , Estrutura Molecular , Ligação Proteica , Receptores de Prostaglandina E Subtipo EP1 , Relação Estrutura-AtividadeRESUMO
We describe the medicinal chemistry approach that generated a novel indole series of EP(1) receptor antagonists. The SAR of this new template was evaluated and culminated in the identification of compound 12g which demonstrated in vivo efficacy in a preclinical model of inflammatory pain.
Assuntos
Indóis/síntese química , Indóis/farmacologia , Receptores de Prostaglandina E/antagonistas & inibidores , Receptores de Prostaglandina E/metabolismo , Animais , Humanos , Ligação de Hidrogênio , Indóis/química , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Estrutura Molecular , Ratos , Receptores de Prostaglandina E Subtipo EP1 , Relação Estrutura-Atividade , Tiazóis/químicaRESUMO
Replacement of the carboxylic acid group in a series of previously described methylene-linked pyrazole EP(1) receptor antagonists led to the discovery of amide, reversed amide and carbamate derivatives. Two compounds, 10a and 10b, were identified as brain penetrant compounds and both demonstrated efficacy in the CFA model of inflammatory pain.
Assuntos
Analgésicos/síntese química , Analgésicos/farmacologia , Pirazóis/síntese química , Pirazóis/farmacologia , Receptores de Prostaglandina E/antagonistas & inibidores , Analgésicos/química , Animais , Encéfalo/efeitos dos fármacos , Sistema Nervoso Central/efeitos dos fármacos , Técnicas de Química Combinatória , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Estrutura Molecular , Medição da Dor , Pirazóis/química , Ratos , Receptores de Prostaglandina E Subtipo EP1 , Relação Estrutura-AtividadeRESUMO
The discovery of a series of selective EP1 receptor antagonists based on a 1,2-diarylcyclopentene template is described. After defining the structural requirements for EP1 potency and selectivity, heterocyclic rings were incorporated to reduce logD and improve in vitro pharmacokinetic properties. The 2,6-substituted pyridines and pyridazines gave an appropriate balance of potency, in vivo pharmacokinetic properties and a low potential for inhibiting a range of CYP450 enzymes. From this series, GW848687X was shown to have an excellent profile in models of inflammatory pain and was selected as a development candidate.
Assuntos
Alprostadil/metabolismo , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/farmacologia , Ciclopentanos/síntese química , Ciclopentanos/farmacologia , Inflamação/tratamento farmacológico , Dor/tratamento farmacológico , Piridinas/síntese química , Piridinas/farmacologia , Receptores de Prostaglandina E/antagonistas & inibidores , Animais , Anti-Inflamatórios não Esteroides/farmacocinética , Disponibilidade Biológica , Sistema Enzimático do Citocromo P-450/metabolismo , Cães , Relação Dose-Resposta a Droga , Adjuvante de Freund , Meia-Vida , Inflamação/induzido quimicamente , Inflamação/complicações , Dor/etiologia , RatosRESUMO
We describe the generation of novel EP(1) receptor antagonists by investigation of thiophene isosteres. In addition, we disclose preliminary in vitro and in vivo DMPK for selected compounds.