RESUMO
Recent literature reports highlight the importance of the renal outer medullary potassium (ROMK) channel in renal sodium and potassium homeostasis and emphasize the potential impact that ROMK inhibitors could have as a novel mechanism diuretic in heart failure patients. A series of piperazine-based ROMK inhibitors were designed and optimized to achieve excellent ROMK potency, hERG selectivity, and ADME properties, which led to the identification of compound 28 (BMS-986308). BMS-986308 demonstrated efficacy in the volume-loaded rat diuresis model as well as promising in vitro and in vivo profiles and was therefore advanced to clinical development.
Assuntos
Insuficiência Cardíaca , Bloqueadores dos Canais de Potássio , Animais , Insuficiência Cardíaca/tratamento farmacológico , Humanos , Ratos , Bloqueadores dos Canais de Potássio/uso terapêutico , Bloqueadores dos Canais de Potássio/farmacologia , Bloqueadores dos Canais de Potássio/química , Bloqueadores dos Canais de Potássio/farmacocinética , Bloqueadores dos Canais de Potássio/síntese química , Relação Estrutura-Atividade , Canais de Potássio Corretores do Fluxo de Internalização/antagonistas & inibidores , Canais de Potássio Corretores do Fluxo de Internalização/metabolismo , Descoberta de Drogas , Diurese/efeitos dos fármacos , Piperazinas/farmacologia , Piperazinas/química , Piperazinas/uso terapêutico , Piperazinas/síntese química , Piperazinas/farmacocinética , Masculino , Ratos Sprague-DawleyRESUMO
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/farmacologiaRESUMO
Using dimethylsulfoxonium methylide as the methylene transfer reagent, 2a,8b-dihydrobenzo[b]cyclobute[d]pyran-3-ones were converted into 2,2'-biphenol derivatives as major products and dihydrodibenzofurans as minor products. The reaction mechanism was extrapolated from a deuteration experiment with CD2=S(O)(CD3)2.
Assuntos
Ciclobutanos/química , Dibenzofuranos/síntese química , Fenóis/síntese química , Compostos de Sulfônio/química , Dibenzofuranos/química , Estrutura Molecular , Fenóis/químicaRESUMO
By applying a skeleton transformation reaction using dimethylsulfoxonium methylide, a novel reaction was identified by which 5,6,7,8-tetrahydrocoumarin with the electron-withdrawing group at C3 was led to the spirobicyclo[3.1.0]hexane-cyclohexane derivative. Moreover, by establishing the scope of this reaction, it was confirmed that it is possible to apply this reaction to not only ring-fused α-pyrone derivatives but also alkyl-chain-substituted α-pyrone derivatives in moderate to good yields.
Assuntos
Compostos Bicíclicos com Pontes/síntese química , Hexanos/química , Pironas/química , Compostos de Espiro/síntese química , Compostos de Sulfônio/química , Compostos Bicíclicos com Pontes/química , Estrutura Molecular , Compostos de Espiro/química , EstereoisomerismoRESUMO
The structure-based design, synthesis, and X-ray structure of protein-ligand complexes of exceptionally potent and selective ß-secretase inhibitors are described. The inhibitors are designed specifically to interact with S(1)' active site residues to provide selectivity over memapsin 1 and cathepsin D. Inhibitor 5 has exhibited exceedingly potent inhibitory activity (K(i) = 17 pM) and high selectivity over BACE 2 (>7000-fold) and cathepsin D (>250000-fold). A protein-ligand crystal structure revealed important molecular insight into these selectivities. These interactions may serve as an important guide to design selectivity over the physiologically important aspartic acid proteases.
Assuntos
Amidas/síntese química , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Indóis/síntese química , Ácidos Ftálicos/síntese química , Sulfonamidas/síntese química , Amidas/química , Amidas/farmacologia , Linhagem Celular Tumoral , Permeabilidade da Membrana Celular , Cristalografia por Raios X , Desenho de Fármacos , Humanos , Indóis/química , Indóis/farmacologia , Ligantes , Modelos Moleculares , Estrutura Molecular , Ácidos Ftálicos/química , Ácidos Ftálicos/farmacologia , Estereoisomerismo , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacologiaRESUMO
The first asymmetric total synthesis of (-)-Linderol A, a potent inhibitor of melanin biosynthesis of cultured B-16 melanoma cells, has been achieved via two key reactions: a diastereoselective [2+2] photocycloaddition of a coumarin-3-carboxylate bearing a chiral auxiliary with 3-methyl-1-butene and a subsequent stereoconvergent transformation of the photoadducts with use of dimethylsulfoxonium methylide to afford a tetrahydrodibenzofuran derivative.