RESUMO
A series of P2-modified, orally active peptidic inhibitors of human neutrophil elastase (HNE) are reported. These pentafluoroethyl ketone-based inhibitors were designed using pentafluoroethyl ketone 1 as a model. Rational structural modifications were made at the P3, P2, and activating group (AG) portions of 1 based on structure-activity relationships (SAR) developed from in vitro (measured Ki) data and information provided by modeling studies that docked inhibitor 1 into the active site of HNE. The modeling-based design was corroborated with X-ray crystallographic analysis of the complex between 1 and porcine pancreatic elastase (PPE) and subsequently the complex between 1 and HNE.
Assuntos
Desenho de Fármacos , Cetonas , Elastase de Leucócito/antagonistas & inibidores , Neutrófilos/enzimologia , Oligopeptídeos , Inibidores de Serina Proteinase , Administração Oral , Animais , Azetidinas/química , Sítios de Ligação , Cricetinae , Cristalografia por Raios X , Fluorocarbonos/química , Fluorocarbonos/metabolismo , Fluorocarbonos/farmacologia , Hemorragia/induzido quimicamente , Hemorragia/enzimologia , Hemorragia/prevenção & controle , Humanos , Isoquinolinas/química , Cetonas/síntese química , Cetonas/química , Cetonas/metabolismo , Cetonas/farmacologia , Elastase de Leucócito/metabolismo , Pneumopatias/induzido quimicamente , Pneumopatias/enzimologia , Pneumopatias/prevenção & controle , Modelos Moleculares , Conformação Molecular , Oligopeptídeos/síntese química , Oligopeptídeos/química , Oligopeptídeos/metabolismo , Oligopeptídeos/farmacologia , Elastase Pancreática/antagonistas & inibidores , Elastase Pancreática/metabolismo , Prolina/análogos & derivados , Prolina/química , Inibidores de Serina Proteinase/síntese química , Inibidores de Serina Proteinase/química , Inibidores de Serina Proteinase/metabolismo , Inibidores de Serina Proteinase/farmacologia , Relação Estrutura-Atividade , SuínosRESUMO
Design modifications to the lead HIV-PR inhibitor 1 (MDL 73,669, Ki = 5 nM) have been postulated based on a computational model of the 1/HIV-PR complex. A novel macrocyclic inhibitor 8 (MDL 104,168) wherein the P1 and P3 side chains of the original acyclic inhibitor have been joined retains good biological activity (Ki = 20 nM). NMR analysis of the precursor alcohol (S)-7 shows the conformation of the cyclic region to be very similar to that observed in the enzyme-bound 8 as determined by the computational model. Consistency of the computational model with NMR data and in vacuo molecular dynamics simulations provide the basis for postulating further modifications of the cyclic inhibitor expected to optimize its interactions with HIV-PR.
Assuntos
Dipeptídeos/química , Inibidores da Protease de HIV/química , Peptídeos Cíclicos/química , Sequência de Aminoácidos , Dipeptídeos/farmacologia , Desenho de Fármacos , Inibidores da Protease de HIV/farmacologia , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Dados de Sequência Molecular , Peptídeos Cíclicos/farmacologiaRESUMO
N-Hydroxy-alpha-(2-hydroxyethoxy)-1(2H)-pyrimidineacetamides 1-3 were synthesized as potential antitumor agents whose mechanism of action would involve inhibition of ribonucleoside diphosphate reductase (RDPR, EC 1.17.4.1). Acyclonucleoside esters 6-8 were prepared by the stannic chloride catalyzed reaction of methyl chloro[2-(phenylmethoxy)ethoxy]acetate (5) with various silylated pyrimidines, generated in situ from the bases and bis(trimethylsilyl)acetamide. Catalytic didebenzylation of hydroxamate 11 gave 1, while 2 and 3 were synthesized by the reaction of lactones 14 and 22, respectively, with hydroxylamine. In vitro acyclonucleoside hydroxamic acids 1-3 were 3-10-fold less potent than hydroxyurea against calf thymus cytidine diphosphate reductase. 5-Fluorouracil derivative 2 is nearly equipotent with hydroxyurea in inhibiting the growth of HeLa cells, while 1 is a much weaker inhibitor and cytidine derivative 3 is devoid of activity at 200 micrograms/mL.
