RESUMO
Multiple regions of the 3-oxazolidinedione-6-naphthyl-pyridinone series identified via high throughput screening were explored. SAR studies of these regions including the left-hand side oxazolidinedione moiety, α-substituent on the oxazolidinedione ring, central pyridinone core, and substituents on the central pyridinone core led to the discovery of potent EP(3) receptor antagonists such as compound 29 which possesses outstanding rat pharmacokinetic properties. Synthesis and SAR of these novel compounds and DMPK properties of representative compounds are discussed.
Assuntos
Oxazóis/síntese química , Piridonas/síntese química , Receptores de Prostaglandina E Subtipo EP3/antagonistas & inibidores , Administração Oral , Animais , Disponibilidade Biológica , Humanos , Estrutura Molecular , Oxazóis/química , Oxazóis/farmacologia , Ligação Proteica/efeitos dos fármacos , Piridonas/química , Piridonas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de Prostaglandina E Subtipo EP3/química , Relação Estrutura-AtividadeRESUMO
A series of phenoxyacetic acids as subtype selective and potent hPPARδ partial agonists is described. Many analogues were readily accessible via a single solution-phase synthetic route which resulted in the rapid identification of key structure-activity relationships (SAR), and the discovery of two potent exemplars which were further evaluated in vivo. Details of the SAR, optimization, and in vivo efficacy of this series are presented herein.
Assuntos
Acetatos/química , PPAR delta/agonistas , Acetatos/síntese química , Acetatos/farmacocinética , Animais , Sítios de Ligação , Cristalografia por Raios X , Humanos , Masculino , Camundongos , Microssomos Hepáticos/metabolismo , PPAR delta/metabolismo , Ratos , Relação Estrutura-AtividadeRESUMO
Further optimization of the biaryl amide series via extensively exploring structure-activity relationships resulted in potent and subtype selective M(1) agonists exemplified by compounds 9a and 9j with good rat PK properties including CNS penetration. Synthesis, structure-activity relationships, subtype selectivity for M(1) over M(2-5), and DMPK properties of these novel compounds are described.
Assuntos
Amidas/síntese química , Amidas/farmacocinética , Hidrocarbonetos Aromáticos/síntese química , Hidrocarbonetos Aromáticos/farmacocinética , Receptor Muscarínico M1/agonistas , Amidas/farmacologia , Animais , Barreira Hematoencefálica/metabolismo , Sistema Nervoso Central/metabolismo , Descoberta de Drogas , Hidrocarbonetos Aromáticos/farmacologia , Estrutura Molecular , Ratos , Relação Estrutura-Atividade , Distribuição TecidualRESUMO
Biaryl amides were discovered as novel and subtype selective M(1) muscarinic acetylcholine receptor agonists. The identification, synthesis, and initial structure-activity relationships that led to compounds 3j and 4c, possessing good M(1) agonist potency and intrinsic activity, and subtype selectivity for M(1) over M(2-5), are described.
Assuntos
Amidas/síntese química , Hidrocarbonetos Aromáticos/síntese química , Receptor Muscarínico M1/agonistas , Amidas/farmacologia , Descoberta de Drogas , Hidrocarbonetos Aromáticos/farmacologia , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Exploration of multiple regions of a bi-aryl amine template led to the identification of highly potent M(3) muscarinic acetylcholine receptor antagonists such as 14 (pA(2)=11.0) possessing good sub-type selectivity for M(3) over M(2). The structure-activity relationships (SAR) and optimization of the bi-aryl amine series are described.
Assuntos
Aminas/síntese química , Química Farmacêutica/métodos , Receptor Muscarínico M3/antagonistas & inibidores , Amidas/química , Aminas/farmacologia , Asma/tratamento farmacológico , Desenho de Fármacos , Elétrons , Humanos , Concentração Inibidora 50 , Cinética , Modelos Químicos , Estrutura Molecular , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Receptor Muscarínico M3/química , Relação Estrutura-AtividadeRESUMO
A series of 2-aminomethyl piperidines has been discovered as novel urotensin-II receptor antagonists. The synthesis, initial structure-activity relationships, and optimization of the initial hit that resulted in the identification of potent, cross-species active, and functional urotensin-II receptor antagonists such as 1a and 11a are described.
Assuntos
Metilaminas/farmacologia , Piperidinas/farmacologia , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Vasoconstritores/farmacologia , Sítios de Ligação , Humanos , Metilaminas/síntese química , Modelos Químicos , Piperidinas/síntese química , Estereoisomerismo , Relação Estrutura-Atividade , Vasoconstritores/síntese químicaRESUMO
SAR exploration of multiple regions of a tyrosine urea template led to the identification of very potent muscarinic acetylcholine receptor antagonists such as 10b with good subtype selectivity for M(3) over M(1). The structure-activity relationships (SAR) and optimization of the tyrosine urea series are described.
Assuntos
Química Farmacêutica/métodos , Antagonistas Muscarínicos/síntese química , Receptores Muscarínicos/química , Tirosina/química , Ureia/química , Asma/tratamento farmacológico , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Modelos Químicos , Estrutura Molecular , Antagonistas Muscarínicos/farmacologia , Sais/química , Relação Estrutura-AtividadeRESUMO
Lead compound 1 was successfully redesigned to provide compounds with improved pharmacokinetic profiles for this series of human urotensin-II antagonists. Replacement of the 2-pyrrolidinylmethyl-3-phenyl-piperidine core of 1 with a substituted N-methyl-2-(1-pyrrolidinyl)ethanamine core as in compound 7 resulted in compounds with improved oral bioavailability in rats. The relationship between stereochemistry and selectivity for hUT over the kappa-opioid receptor was also explored.
Assuntos
Química Farmacêutica/métodos , Urotensinas/antagonistas & inibidores , Administração Oral , Animais , Encéfalo/metabolismo , Cromatografia Líquida de Alta Pressão , Diaminas/química , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Modelos Químicos , Ratos , Receptores Opioides kappa/química , Estereoisomerismo , Relação Estrutura-Atividade , Urotensinas/químicaRESUMO
Virtual screening of the corporate compound collection yielded compound 1 as a subtype selective muscarinic M1 receptor agonist hit. Initial optimization of the N-capping group of the central piperidine ring resulted in compounds 2 and 3 with significantly improved potency and selectivity. Subsequent optimization of substituents on the phenyl ring of the benzimidazolone moiety led to the discovery of novel muscarinic M1 receptor agonists 4 and 5 with excellent potency, general and subtype selectivity, and pharmacokinetic (PK) properties including good central nervous system (CNS) penetration and oral bioavailability. Compound 5 showed robust in vivo activities in animal models of cognition enhancement. The combination of high potency, excellent selectivity, and good PK properties makes compounds 4 and 5 valuable tool compounds for investigating and validating potential therapeutic benefits resulting from selective M1 activation.
RESUMO
High-throughput screening and subsequent optimization led to the discovery of novel 3-oxazolidinedione-6-aryl-pyridinones exemplified by compound 2 as potent and selective EP3 antagonists with excellent pharmacokinetic properties. Compound 2 was orally active and showed robust in vivo activities in overactive bladder models. To address potential bioactivation liabilities of compound 2, further optimization resulted in compounds 9 and 10, which maintained excellent potency, selectivity, and pharmacokinetic properties and showed no bioactivation liability in glutathione trapping studies. These highly potent, selective, and orally active EP3 antagonists are excellent tool compounds for investigating and validating potential therapeutic benefits from selectively inhibiting the EP3 receptor.
RESUMO
A series of novel biphenyl piperazines was discovered as highly potent muscarinic acetylcholine receptor antagonists via high throughput screening and subsequent optimization. Compound 5c with respective 500- and 20-fold subtype selectivity for M3 over M2 and M1 exhibited excellent inhibitory activity and long duration of action in a bronchoconstriction in vivo model in mice via intranasal administration. The novel inhaled mAChR antagonists are potentially useful therapeutic agents for the treatment of chronic obstructive pulmonary disease.
Assuntos
Broncoconstrição/efeitos dos fármacos , Broncodilatadores/farmacologia , Piperazinas/farmacologia , Receptores Muscarínicos/efeitos dos fármacos , Administração Intranasal , Animais , Testes de Provocação Brônquica , Broncoconstritores/farmacologia , Broncodilatadores/síntese química , Broncodilatadores/química , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Cloreto de Metacolina/farmacologia , Camundongos , Estrutura Molecular , Piperazinas/síntese química , Piperazinas/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
High throughput screening and subsequent optimization led to the discovery of novel quaternary ammonium salts as highly potent muscarinic acetylcholine receptor antagonists with excellent selectivity. Compounds 8a, 13a, and 13b showed excellent inhibitory activity and long duration of action in bronchoconstriction in vivo models in two species via intranasal or intratracheal administration. The novel inhaled muscarinic receptor antagonists are potentially useful therapeutic agents for the treatment of chronic obstructive pulmonary disease and other bronchoconstriction disorders.