RESUMO
Potent and selective thrombin inhibitors have been prepared with a piperazinedione template and L-amino acids. Likewise, incorporation of D-amino acids led to potent inhibitors with a novel mode of binding. Herein, the structure activity relationships and structural aspects of these compounds will be described.
Assuntos
Antitrombinas/síntese química , Desenho de Fármacos , Piperazinas/síntese química , Antitrombinas/química , Antitrombinas/farmacologia , Cristalografia por Raios X , Estrutura Molecular , Piperazinas/química , Piperazinas/farmacologia , Relação Estrutura-AtividadeRESUMO
A series of esters of 1,4-disubstituted tetrahydropyridine carboxylic acids (I) has been synthesized and characterized as potential m1 selective muscarinic receptor antagonists. The affinity of these compounds for the five human muscarinic receptor subtypes (Hm1-Hm5) was determined by the displacement of [3H]-NMS binding using membranes from transfected Chinese hamster ovarian cells. One of the most potent and selective compounds of this series is an analogue of I [11, R1 = (CH2)5CH3], which has an IC50 value of 27.3 nM at the m1 receptor and possesses 100-fold (m2), 48-fold (m3), 74-fold (m4), and 19-fold (m5) selectivities at the other receptors. Thus, this analogue appears to be more selective on the basis of binding than the prototypical m1 antagonist, pirenzepine. Functional data, such as the inhibition of carbachol-stimulated phosphatidylinositol hydrolysis, on selected analogues confirmed the muscarinic antagonistic properties of this chemical series.
Assuntos
Antagonistas Muscarínicos/química , Animais , Células CHO , Cricetinae , Humanos , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Estrutura Molecular , Antagonistas Muscarínicos/classificação , Antagonistas Muscarínicos/farmacologia , Relação Estrutura-AtividadeRESUMO
Our interest in the area of m4 muscarinic antagonists had led us to study a series of benzoxazine isoquinolines. One of the most potent and selective compounds of this series is example 1 with an IC50 value of 90.7 nM at m4 receptors, and 72-fold (m1), 38-fold (m2), 10-fold (m3), and 82-fold (m5) more selective compared to the other receptors. The synthesis and receptor binding affinity of analogs of 1 are reported.
Assuntos
Isoquinolinas/química , Antagonistas Muscarínicos/química , Receptores Muscarínicos/efeitos dos fármacos , Isoquinolinas/metabolismo , Isoquinolinas/farmacologia , Antagonistas Muscarínicos/metabolismo , Antagonistas Muscarínicos/farmacologia , Ligação Proteica , Receptor Muscarínico M4 , Receptores Muscarínicos/metabolismoRESUMO
Peptidomimetic inhibitors of general structure 1 have been prepared. Optimization of the binding affinities of these compounds through variation of the P3 hydrophobic residue is described. Selected substituted bicylic lactams displayed interesting pharmacological profiles both in vitro and in vivo.
