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1.
J Med Chem ; 60(9): 3795-3803, 2017 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-28418664

RESUMO

We have recently disclosed 5-phenyl-N-(pyridin-2-ylmethyl)-2-(pyrimidin-5-yl)quinazolin-4-amine 1 as a potent IKur current blocker with selectivity versus hERG, Na and Ca channels, and an acceptable preclinical PK profile. Upon further characterization in vivo, compound 1 demonstrated an unacceptable level of brain penetration. In an effort to reduce the level of brain penetration while maintaining the overall profile, SAR was developed at the C2' position for a series of close analogues by employing hydrogen bond donors. As a result, 5-[5-phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl]pyridine-3-sulfonamide (25) was identified as the lead compound in this series. Compound 25 showed robust effects in rabbit and canine pharmacodynamic models and an acceptable cross-species pharmacokinetic profile and was advanced as the clinical candidate. Further optimization of 25 to mitigate pH-dependent absorption resulted in identification of the corresponding phosphoramide prodrug (29) with an improved solubility and pharmacokinetic profile.


Assuntos
Fibrilação Atrial/tratamento farmacológico , Bloqueadores dos Canais de Potássio/uso terapêutico , Quinazolinas/uso terapêutico , Bloqueadores dos Canais de Sódio/uso terapêutico , Sulfonamidas/uso terapêutico , Animais , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Cães , Espectrometria de Massas , Bloqueadores dos Canais de Potássio/farmacologia , Espectroscopia de Prótons por Ressonância Magnética , Quinazolinas/química , Quinazolinas/farmacologia , Coelhos , Bloqueadores dos Canais de Sódio/farmacologia , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacologia
2.
ACS Med Chem Lett ; 7(9): 831-4, 2016 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-27660686

RESUMO

A new series of phenylquinazoline inhibitors of Kv 1.5 is disclosed. The series was optimized for Kv 1.5 potency, selectivity versus hERG, pharmacokinetic exposure, and pharmacodynamic potency. 5-Phenyl-N-(pyridin-2-ylmethyl)-2-(pyrimidin-5-yl)quinazolin-4-amine (13k) was identified as a potent and ion channel selective inhibitor with robust efficacy in the preclinical rat ventricular effective refractory period (VERP) model and the rabbit atrial effective refractory period (AERP) model.

3.
Bioorg Med Chem Lett ; 25(21): 4983-4986, 2015 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-25801931

RESUMO

Phenethyl aminoheterocycles like compound 1 were known to be potent I(Kur) blockers although they lacked potency in vivo. Modification of the heterocycle led to the design and synthesis of pseudosaccharin amines. Compounds such as 14, 17d and 21c were found to be potent K(V)1.5 blockers and selective over other cardiac ion channels. These compounds had potent pharmacodynamic activity, however, they also showed off-target activities such as hemodynamic effects.


Assuntos
Aminas/farmacologia , Canal de Potássio Kv1.5/antagonistas & inibidores , Bloqueadores dos Canais de Potássio/farmacologia , Aminas/síntese química , Aminas/química , Animais , Pressão Sanguínea/efeitos dos fármacos , Cicloexanos/química , Cicloexanos/farmacologia , Relação Dose-Resposta a Droga , Humanos , Canal de Potássio Kv1.5/metabolismo , Camundongos , Estrutura Molecular , Bloqueadores dos Canais de Potássio/síntese química , Bloqueadores dos Canais de Potássio/química , Coelhos , Ratos , Compostos de Espiro/química , Compostos de Espiro/farmacologia , Relação Estrutura-Atividade
5.
J Med Chem ; 55(7): 3036-48, 2012 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-22409629

RESUMO

Previously disclosed dihydropyrazolopyrimidines are potent and selective blockers of I(Kur) current. A potential liability with this chemotype is the formation of a reactive metabolite which demonstrated covalent binding to protein in vitro. When substituted at the 2 or 3 position, this template yielded potent I(Kur) inhibitors, with selectivity over hERG which did not form reactive metabolites. Subsequent optimization for potency and PK properties lead to the discovery of ((S)-5-(methoxymethyl)-7-(1-methyl-1H-indol-2-yl)-2-(trifluoromethyl)-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)((S)-2-(3-methylisoxazol-5-yl)pyrrolidin-1-yl)methanone (13j), with an acceptable PK profile in preclinical species and potent efficacy in the preclinical rabbit atrial effective refractory period (AERP) model.


Assuntos
Canal de Potássio Kv1.5/antagonistas & inibidores , Pirazóis/síntese química , Pirimidinas/síntese química , Animais , Cães , Coração/efeitos dos fármacos , Coração/fisiologia , Humanos , Pirazóis/farmacocinética , Pirazóis/farmacologia , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Coelhos , Ratos , Período Refratário Eletrofisiológico/efeitos dos fármacos , Estereoisomerismo , Relação Estrutura-Atividade
8.
Bioorg Med Chem Lett ; 18(8): 2714-8, 2008 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-18374568

RESUMO

The design and synthesis of a series of highly functionalized pyrano-[2,3b]-pyridines is described. These compounds were assayed for their ability to block the I(Kur) channel encoded by the gene hKV1.5 in patch-clamped L-929 cells. Six of the compounds in this series showed sub-micromolar activity, the most potent being 4-(4-ethyl-benzenesulfonylamino)-3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3b]-pyridine-6-carboxylic acid ethyl-phenyl-amide with an IC(50) of 378 nM.


Assuntos
Bloqueadores dos Canais de Potássio/síntese química , Bloqueadores dos Canais de Potássio/farmacologia , Piranos/química , Piridinas/síntese química , Piridinas/farmacologia , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Camundongos , Estrutura Molecular , Bloqueadores dos Canais de Potássio/química , Piridinas/química , Relação Estrutura-Atividade
9.
Bioorg Med Chem ; 15(18): 6182-92, 2007 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-17596950

RESUMO

We describe the development of a computational model for the prediction of the inhibition of K(+) flow through the hERG ion channel. Using a collection of 1075 discovery compounds with hERG inhibition measured in our standard patch-clamp electrophysiology assay, molecular features important for drug-induced inhibition were identified using a combination of statistical inference algorithms and manual hypothesis generation and testing. While many of the features used in the model reflect those referenced in the literature, several aspects of the model provide new insight into the role of physicochemical properties, electrostatics, and novel pharmacophores in hERG inhibition. Coefficients for these 10 features were then determined by least median squares regression, resulting in a model with an R(2) approximately 0.66 and RMS error (RMSe) of 0.47 log units for an external test set. Significant additional validation performed using a large collection of subsequent discovery data has been very encouraging with an R(2)=0.54 and an RMSe of 0.63 log units. The performance of the model across several different chemotypes is demonstrated and discussed.


Assuntos
Simulação por Computador , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Canais de Potássio Éter-A-Go-Go/metabolismo , Preparações Farmacêuticas/metabolismo , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/química , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Técnicas de Patch-Clamp , Ligação Proteica , Relação Quantitativa Estrutura-Atividade
11.
Bioorg Med Chem Lett ; 14(1): 99-102, 2004 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-14684307

RESUMO

Class III anti-arrhythmic drugs (e.g., dofetilide) prolong cardiac action potential duration (APD) by blocking the fast component of the delayed rectifier potassium current (I(Kr)). The block of I(Kr) can result in life threatening ventricular arrhythmias (i.e., torsades de pointes). Unlike I(Kr), the role of the slow component of the delayed rectifier potassium current (I(Ks)) becomes significant only at faster heart rate. Therefore selective blockers of I(Ks) could prolong APD with a reduced propensity to cause pro-arrhythmic side effects. This report describes structure-activity relationships (SARs) of a series of I(Ks) inhibitors derived from 6-alkoxytetralones with good in vitro activity (IC(50) > or =30 nM) and up to 40-fold I(Ks)/I(Kr) selectivity.


Assuntos
Amino Álcoois/farmacologia , Bloqueadores dos Canais de Potássio/farmacologia , Canais de Potássio de Abertura Dependente da Tensão da Membrana , Canais de Potássio/fisiologia , Tetra-Hidronaftalenos/farmacologia , Amino Álcoois/química , Animais , Canais de Potássio de Retificação Tardia , Cobaias , Cetonas/química , Cetonas/farmacologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/fisiologia , Bloqueadores dos Canais de Potássio/química , Tetra-Hidronaftalenos/química
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