26 research outputs found
Irreversible inhibitors of serine proteases based on the \03B2-lactam scaffold as potential drug candidates
Tese de doutoramento, FarmĂĄcia (QuĂmica FarmacĂȘutica e TerapĂȘutica), 2009, Universidade de Lisboa, Faculdade de FarmĂĄciaDisponĂvel no documentoCentro de Estudos de CiĂȘncias FarmacĂȘuticas (CECF)/iMed.UL (Institute for Medicines and Pharmaceutical Sciences), Faculdade de FarmĂĄcia da Universidade de Lisboa. Fundação para a CiĂȘncia e a Tecnologia (SFRH/BD/17534/2004 e projecto PTDC/QUI/64056/2006
Irreversible inhibitors of serine proteases based on the \03B2-lactam scaffold as potential drug candidates
Tese de doutoramento, FarmĂĄcia (QuĂmica FarmacĂȘutica e TerapĂȘutica), 2009, Universidade de Lisboa, Faculdade de FarmĂĄciaDisponĂvel no documentoCentro de Estudos de CiĂȘncias FarmacĂȘuticas (CECF)/iMed.UL (Institute for Medicines and Pharmaceutical Sciences), Faculdade de FarmĂĄcia da Universidade de Lisboa. Fundação para a CiĂȘncia e a Tecnologia (SFRH/BD/17534/2004 e projecto PTDC/QUI/64056/2006
Recommended from our members
4-Oxo-ÎČ-lactams (Azetidine-2,4-diones) Are Potent and Selective Inhibitors of Human Leukocyte Elastase
Human leukocyte elastase (HLE) is a serine protease stored in and secreted from neutrophils that plays a determinant role in the pathogenesis of several lung diseases. 4-Oxo-ÎČ-lactams, previously reported as acylating agents of porcine pancreatic elastase, were found to be selective and potent inhibitors of HLE. Structureâactivity relationship analysis showed that inhibitory activity is very sensitive to the nature of C-3 substituents, with small alkyl substituents such as a gem-diethyl group improving the inhibitory potency when compared to gem-methyl benzyl or ethyl benzyl counterparts. 4-Oxo-ÎČ-lactams containing a heteroarylthiomethyl group on the para position of an N1-aryl moiety afforded highly potent and selective inhibition of HLE, even at a very low inhibitor to enzyme ratio, as shown by the kon value of 3.24 Ă 106 Mâ1 sâ1 for 6f. The corresponding ortho isomers were 40- to 90-fold less potent
Clickable 4-Oxo-ÎČ-lactam-Based Selective Probing for Human Neutrophil Elastase Related Proteomes
Recommended from our members
Crystallization and preliminary diffraction studies of porcine pancreatic elastase in complex with a novel inhibitor
Porcine pancreatic elastase (PPE) was crystallized in complex with a novel inhibitor at pH 5 and X-ray diffraction data were collected at a synchrotron source to 1.66 angstrom. Crystals belong to the orthorhombic space group P2(1)2(1)2(1), with unit cell parameters a = 50.25 angstrom, b = 57.94 angstrom and c = 74.69 angstrom. PPE is often used as model for drug target, due to its structural homology with the important therapeutic target human leukocyte elastase (HLE). Elastase is a serine protease that belongs to the chymotrypsin family, which has the ability to degrade elastin, an important component in connective tissues. Excessive elastin proteolysis leads to a number of pathological diseases
Azetidine-2,4-diones (4-Oxo-ÎČ-lactams) as Scaffolds for Designing Elastase Inhibitors
A new class of inhibitors 4-oxo-beta-lactams (azetidine-2,4-diones), containing the required structural elements for molecular recognition, inhibit porcine pancreatic elastase (PPE) but show a dramatically lower reactivity toward hydroxide compared with the analogous inhibitors 3-oxo-beta-sultams. Inhibition is the result of acylation of the active site serine and electron-withdrawing substituents at the N-(4-aryl) position in 3,3-diethyl-N-aryl derivatives increasing the rate of enzyme acylation and generating a Hammett p-value of 0.65. Compared with a p-value of 0.96 for the rates of alkaline hydrolysis of the same series, this is indicative of an earlier transition state for the enzyme-catalyzed reaction. Docking studies indicate favorable noncovalent interactions of the inhibitor with the enzyme. Compound 2i, the most potent inhibitor against PPE, emerged as a very potent HLE inhibitor, with a second-order rate for enzyme inactivation of similar to 5 x 10(5) M-1 s(-1)