RESUMO
A novel series of N-heteroaryl 4'-(2-furyl)-4,5'-bipyrimidin-2'-amines has been identified as potent and selective A(2B) adenosine receptor antagonists. In particular, compound 5 showed high affinity for the A(2B) receptor (Ki = 17 nM), good selectivity (IC(50): A(1) > 1000 nM, A(2A) > 2500 nM, A3 > 1000 nM), displayed a favorable pharmacokinetic profile in preclinical species, and showed efficacy in functional in vitro models.
Assuntos
Antagonistas do Receptor A2 de Adenosina , Furanos/síntese química , Piridinas/síntese química , Pirimidinas/síntese química , Animais , Linhagem Celular , Cricetinae , Cricetulus , Cães , Furanos/farmacocinética , Furanos/farmacologia , Camundongos , Piridinas/farmacocinética , Piridinas/farmacologia , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Ensaio Radioligante , Ratos , Relação Estrutura-AtividadeRESUMO
A series of indolylpiperidinyl derivatives were prepared and evaluated for their activity as histamine H(1) antagonists. Structure-activity relationship studies were directed toward improving in vivo activity and pharmacokinetic profile of our first lead (1). Substitution of fluorine in position 6 on the indolyl ring led to higher in vivo activity in the inhibition of histamine-induced cutaneous vascular permeability assay but lower selectivity toward 5HT(2) receptor. Extensive optimization was carried out within this series and a number of histamine H(1) antagonists showing potency and long duration of action in vivo and low brain penetration or cardiotoxic potential were identified. Within this novel series, indolylpiperidines 15, 20, 48,51 and 52 exhibited a long half-life in rat and have been selected for further preclinical evaluation.
Assuntos
Antagonistas dos Receptores Histamínicos H1/síntese química , Indóis/síntese química , Piperidinas/síntese química , Animais , Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Permeabilidade Capilar/efeitos dos fármacos , Citocromo P-450 CYP3A , Inibidores das Enzimas do Citocromo P-450 , Eletrocardiografia/efeitos dos fármacos , Cobaias , Meia-Vida , Antagonistas dos Receptores Histamínicos H1/farmacologia , Antagonistas dos Receptores Histamínicos H1/toxicidade , Humanos , Técnicas In Vitro , Indóis/farmacologia , Indóis/toxicidade , Masculino , Camundongos , Piperidinas/farmacologia , Piperidinas/toxicidade , Ensaio Radioligante , Ratos , Ratos Wistar , Receptores Adrenérgicos alfa 1/efeitos dos fármacos , Receptores Adrenérgicos alfa 1/metabolismo , Receptores Histamínicos H1/efeitos dos fármacos , Receptores Histamínicos H1/metabolismo , Receptores de Serotonina/efeitos dos fármacos , Receptores de Serotonina/metabolismo , Pele/irrigação sanguínea , Relação Estrutura-AtividadeRESUMO
Following his academic studies at the University of Surrey (UK), Graham Warrellow entered the pharmaceutical industry to pursue a career at the forefront of drug discovery. Following successful spells at Wyeth, Celltech and Almirall, he joined UCB as the Vice President for Chemistry UK. Through this role and as a director at Cyclofluidic, a joint venture of UCB and Pfizer, he has witnessed changing trends in medicinal chemistry R&D over recent years. Dr Warrellow speaks to Isaac Bruce, Commissioning Editor, about industry collaborations, what qualities make for a good medicinal chemist and the future of the pharmaceutical industry.
Assuntos
Indústria Farmacêutica , Pessoal Administrativo , Química Farmacêutica , Comportamento Cooperativo , Descoberta de Drogas , Papel Profissional , Reino UnidoRESUMO
The preparation of the sulfoxide analogues 7, 8, and 9 and their enantiomerically pure forms is discussed as well as their ability to act as prodrugs of the potent and selective sulfone-containing COX-2 inhibitors 1, 2, and 3. Sulfoxide derivatives 7 and 9 were shown to be rapidly transformed in vivo into the corresponding sulfone derivatives 1 and 3, after oral administration to rats.
Assuntos
Inibidores de Ciclo-Oxigenase 2/farmacologia , Ciclo-Oxigenase 2/efeitos dos fármacos , Pró-Fármacos/farmacologia , Sulfonas/farmacologia , Sulfóxidos/farmacologia , Animais , Cristalografia por Raios X , Ciclo-Oxigenase 1/efeitos dos fármacos , Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/química , Avaliação Pré-Clínica de Medicamentos , Humanos , Masculino , Modelos Moleculares , Estrutura Molecular , Pró-Fármacos/síntese química , Pró-Fármacos/química , Ratos , Ratos Wistar , Estereoisomerismo , Relação Estrutura-Atividade , Sulfonas/síntese química , Sulfonas/química , Sulfóxidos/síntese química , Sulfóxidos/químicaRESUMO
The preparation of the sulfoxide analogues 2 and 4, and their enantiomeric pure forms is discussed as well as their potential to act as prodrugs to the potent and selective sulfone-containing COX-2 inhibitors rofecoxib and etoricoxib. Sulfoxides 2 and 4 were shown to be effectively transformed in vivo into rofecoxib and etoricoxib, respectively, after oral administration in rats. In the case of sulfoxide 2, both a slightly improved pharmacokinetic profile and a better pharmacological activity in an arthritis model were seen when compared with rofecoxib.
Assuntos
Inibidores de Ciclo-Oxigenase 2/farmacologia , Lactonas/química , Lactonas/farmacologia , Pró-Fármacos/farmacologia , Piridinas/química , Piridinas/farmacologia , Safrol/análogos & derivados , Sulfonas/química , Sulfonas/farmacologia , Animais , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/sangue , Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/química , Etoricoxib , Humanos , Isomerismo , Lactonas/sangue , Lactonas/síntese química , Masculino , Estrutura Molecular , Pró-Fármacos/síntese química , Pró-Fármacos/química , Pró-Fármacos/farmacocinética , Piridinas/sangue , Piridinas/síntese química , Ratos , Ratos Wistar , Safrol/química , Solubilidade , Sulfonas/sangue , Sulfonas/síntese química , Temperatura , TermodinâmicaRESUMO
The synthesis and structure-activity relationships of piperidinylpyrrolopyridines as potent and selective H(1) antagonists are discussed. It was found that the nature of the acid chain bonded to piperidine was a key feature for maintaining both the duration of action in vivo and lack of sedative properties.
Assuntos
Antagonistas dos Receptores Histamínicos H1/síntese química , Piridinas/síntese química , Administração Oral , Animais , Barreira Hematoencefálica , Permeabilidade Capilar , Cobaias , Antagonistas dos Receptores Histamínicos H1/farmacocinética , Antagonistas dos Receptores Histamínicos H1/farmacologia , Humanos , Concentração Inibidora 50 , Piridinas/farmacocinética , Piridinas/farmacologia , Ratos , Solubilidade , Relação Estrutura-AtividadeRESUMO
SAR studies aimed at improving the rate of clearance of a series of VLA-4 integrin antagonists by the introduction of a 1,3,5-triazine as an amide isostere are described.
Assuntos
Integrina alfa4beta1/antagonistas & inibidores , Fenilalanina/química , Fenilalanina/farmacologia , Triazinas/química , Triazinas/farmacologia , Fenilalanina/análogos & derivados , Relação Estrutura-AtividadeRESUMO
The SAR studies to optimise both potency and rate of clearance in the rat for a series of pyrimidine and pyridine based VLA-4 antagonists are described.
Assuntos
Integrina alfa4beta1/antagonistas & inibidores , Fenilalanina/química , Fenilalanina/farmacologia , Piridinas/química , Piridinas/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , Fenilalanina/análogos & derivados , Relação Estrutura-AtividadeRESUMO
SAR studies aimed at improving the rate of clearance by the incorporation of a 3,4-diamino-3-cyclobutene-1,2-dione group as an amino acid isostere in a series of VLA-4 integrin antagonists are described.
Assuntos
Antialérgicos/antagonistas & inibidores , Ciclobutanos/síntese química , Ciclobutanos/farmacologia , Integrinas/antagonistas & inibidores , Receptores de Retorno de Linfócitos/antagonistas & inibidores , Aminas/química , Animais , Integrina alfa4beta1 , Integrina beta1 , Taxa de Depuração Metabólica , Ratos , Receptores de Antígeno muito Tardio , Relação Estrutura-AtividadeRESUMO
We describe a series of dehydrophenylalanine derivatives where the Z isomers are potent VLA-4 antagonists but are subject to rapid biliary clearance and the E isomers have poor activity but have a slower rate of clearance. These configurationally constrained molecules have led to the design of a novel class of benzodiazepine VLA-4 antagonists.