RESUMO
A peptidomimetic analogue of Pro-Leu-Gly-NH2 (PLG), compound 3, has been synthesized that contains a highly constrained spiro bicyclic type-II beta-turn mimic. Peptidomimetic 3 enhanced the binding of the dopamine receptor agonist ADTN to dopamine receptors by 40% at 10(-6) M. At this same concentration PLG enhanced the binding of ADTN by 26%. Like PLG, 3 exhibited a bell-shaped dose-response curve with the maximum effect occurring at a concentration of 10(-6) M. Because of the highly rigid nature of the spiro bicyclic type-II beta-turn constraint found in 3, these results lend strong support for the hypothesis that the biologically active conformation of PLG is a type-II beta-turn.
Assuntos
Compostos Bicíclicos com Pontes/síntese química , Oligopeptídeos/síntese química , Oligopeptídeos/farmacologia , Receptores Dopaminérgicos/efeitos dos fármacos , Sequência de Aminoácidos , Animais , Compostos Bicíclicos com Pontes/farmacologia , Bovinos , Dopaminérgicos/síntese química , Dopaminérgicos/metabolismo , Dopaminérgicos/farmacologia , Cinética , Dados de Sequência Molecular , Conformação Proteica , Receptores Dopaminérgicos/metabolismo , Tetra-Hidronaftalenos/metabolismo , TrítioRESUMO
Through computationally directed broad screening, a novel 1, 5-diphenylpyrazole (DPP) class of HIV-1 nonnucleoside reverse transcriptase inhibitors (NNRTIs) has been discovered. Compound 2 (PNU-32945) was found to have good activity versus wild-type (IC(50) = 2.3 microM) and delavirdine-resistant P236L (IC(50) = 1.1 microM) reverse transcriptase (RT). Also, PNU-32945 has an ED(50) for inhibition of viral replication in cell cultures of 0.1 microM and was shown to be noncytotoxic with a CC(50) > 10 microM. Structure-activity relationship studies on the 3- and 4-positions of PNU-32945 led to interesting selectivity and activity within the class. In particular, the 3-hydroxyethyl-4-ethyl congener 29 is a potent inhibitor of the P236L mutant (IC(50) = 0.65 microM), whereas it is essentially inactive versus the wild-type enzyme (IC(50) > 50 microM). Furthermore, this compound was significantly more active versus the P236L mutant than delavirdine. The synthesis and RT inhibitory activity of various 3- and 4-substituted analogues are discussed.
Assuntos
Fármacos Anti-HIV/farmacologia , Delavirdina/farmacologia , Transcriptase Reversa do HIV/antagonistas & inibidores , Pirazóis/síntese química , Inibidores da Transcriptase Reversa/síntese química , Resistência Microbiana a Medicamentos , Transcriptase Reversa do HIV/genética , Mutação , Pirazóis/química , Pirazóis/farmacologia , Inibidores da Transcriptase Reversa/química , Inibidores da Transcriptase Reversa/farmacologia , Relação Estrutura-AtividadeRESUMO
Development of resistance to currently approved HIV therapies has continued to fuel research efforts to improve the metabolic stability and spectrum of activity of the (alkylamino)piperidine-containing bis(heteroaryl)piperazine (AAP-BHAP) class of non-nucleoside reverse transcriptase inhibitors (NNRTIs). The synthesis of analogues in which the usual 3-alkylamino substituent on the pyridine ring is replaced by a 3-alkyl substituent led to compounds which retained activity against recombinant P236L and wild-type (WT) reverse transcriptase (RT), while inhibition of the Y181C mutant RT was reduced relative to the activity of the 3-alkylamino-substituted congeners. Testing of representative analogues in an in vitro liver microsome assay indicated that the alkyl substituent would not appreciably improve the metabolic stability of the AAP-BHAP template. In vivo pharmacokinetic evaluation of three compounds confirmed these results in that high systemic clearances were observed. Nevertheless, one compound (13), PNU-103657, possessed oral bioavailability in rats approaching that of the structurally related NNRTI drug delavirdine which is currently on the market for the treatment of HIV infection.
Assuntos
Aminopiridinas/síntese química , Fármacos Anti-HIV/síntese química , Piperidinas/síntese química , Inibidores da Transcriptase Reversa/síntese química , Sulfonamidas/síntese química , Administração Oral , Aminopiridinas/química , Aminopiridinas/farmacocinética , Aminopiridinas/farmacologia , Animais , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/farmacologia , Disponibilidade Biológica , Células Cultivadas , Técnicas In Vitro , Injeções Intravenosas , Masculino , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/enzimologia , Piperidinas/química , Piperidinas/farmacologia , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes/antagonistas & inibidores , Inibidores da Transcriptase Reversa/química , Inibidores da Transcriptase Reversa/farmacocinética , Inibidores da Transcriptase Reversa/farmacologia , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacocinética , Sulfonamidas/farmacologiaRESUMO
The major route of metabolism of the bis(heteroaryl)piperazine (BHAP) class of reverse transcriptase inhibitors (RTIs), atevirdine and delavirdine, is via oxidative N-dealkylation of the 3-ethyl- or 3-isopropylamino substituent on the pyridine ring. This metabolic pathway is also the predominant mode of metabolism of (alkylamino)piperidine BHAP analogs (AAP-BHAPs), compounds wherein a 4-(alkylamino)piperidine replaces the piperazine ring of the BHAPs. The novel AAP-BHAPs possess the ability to inhibit non-nucleoside reverse transcriptase inhibitor (NNRTI) resistant recombinant HIV-1 RT and NNRTI resistant variants of HIV-1. This report describes an approach to preventing this degradation which involves the replacement of the 3-ethyl- or 3-isopropylamino substituent with either a 3-tert-butylamino substituent or a 3-alkoxy substituent. The synthesis, bioactivity and metabolic stability of these analogs is described. The majority of analogs retain inhibitory activities in enzyme and cell culture assays. In general, a 3-ethoxy or 3-isopropoxy substituent on the pyridine ring, as in compounds 10, 20, or 21, resulted in enhanced stabilities. The 3-tert-butylamino substituent was somewhat beneficial in the AAP-BHAP series of analogs, but did not exert a significant effect in the BHAP series. Lastly, the nature of the indole substitution sometimes plays a significant role in metabolic stability, particularly in the BHAP series of analogs.
Assuntos
Piperazinas/síntese química , Piperazinas/farmacologia , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/farmacologia , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/metabolismo , Fármacos Anti-HIV/farmacologia , Sistema Enzimático do Citocromo P-450/farmacologia , HIV-1/enzimologia , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Microssomos Hepáticos/enzimologia , Piperazinas/metabolismo , Inibidores da Transcriptase Reversa/metabolismo , Relação Estrutura-AtividadeRESUMO
A series of new nitrogen-carbon-linked (azolylphenyl)oxazolidinone antibacterial agents has been prepared in an effort to expand the spectrum of activity of this class of antibiotics to include Gram-negative organisms. Pyrrole, pyrazole, imidazole, triazole, and tetrazole moieties have been used to replace the morpholine ring of linezolid (2). These changes resulted in the preparation of compounds with good activity against the fastidious Gram-negative organisms Haemophilus influenzae and Moraxella catarrhalis. The unsubstituted pyrrolyl analogue 3 and the 1H-1,2,3-triazolyl analogue 6 have MICs against H. influenzae = 4 microgram/mL and M. catarrhalis = 2 microgram/mL. Various substituents were also placed on the azole moieties in order to study their effects on antibacterial activity in vitro and in vivo. Interesting differences in activity were observed for many analogues that cannot be rationalized solely on the basis of sterics and position/number of nitrogen atoms in the azole ring. Differences in activity rely strongly on subtle changes in the electronic character of the overall azole systems. Aldehyde, aldoxime, and cyano azoles generally led to dramatic improvements in activity against both Gram-positive and Gram-negative bacteria relative to unsubstituted counterparts. However, amide, ester, amino, hydroxy, alkoxy, and alkyl substituents resulted in no improvement or a loss in antibacterial activity. The placement of a cyano moiety on the azole often generates analogues with interesting antibacterial activity in vitro and in vivo. In particular, the 3-cyanopyrrole, 4-cyanopyrazole, and 4-cyano-1H-1,2,3-triazole congeners 28, 50, and 90 had S. aureus MICs = 0.5-1 microgram/mL and H. influenzae and M. catarrhalis MICs = 2-4 microgram/mL. These analogues are also very effective versus S. aureus and S. pneumoniae in mouse models of human infection with ED(50)s in the range of 1. 2-1.9 mg/kg versus 2.8-4.0 mg/kg for the eperezolid (1) control.
Assuntos
Antibacterianos/síntese química , Azóis/síntese química , Haemophilus influenzae/efeitos dos fármacos , Moraxella catarrhalis/efeitos dos fármacos , Oxazóis/síntese química , Administração Oral , Animais , Antibacterianos/química , Antibacterianos/farmacologia , Azóis/química , Azóis/farmacologia , Humanos , Resistência a Meticilina , Camundongos , Testes de Sensibilidade Microbiana , Oxazóis/química , Oxazóis/farmacologia , Relação Estrutura-AtividadeAssuntos
Antibacterianos/síntese química , Haemophilus influenzae/efeitos dos fármacos , Moraxella catarrhalis/efeitos dos fármacos , Oxazóis/síntese química , Pirazóis/síntese química , Pirróis/síntese química , Administração Oral , Animais , Antibacterianos/química , Antibacterianos/farmacocinética , Antibacterianos/farmacologia , Contagem de Colônia Microbiana , Concentração Inibidora 50 , Injeções Intravenosas , Masculino , Camundongos , Oxazóis/química , Oxazóis/farmacocinética , Oxazóis/farmacologia , Pirazóis/química , Pirazóis/farmacocinética , Pirazóis/farmacologia , Pirróis/química , Pirróis/farmacocinética , Pirróis/farmacologia , Ratos , Ratos Sprague-Dawley , Infecções Estafilocócicas/tratamento farmacológico , Relação Estrutura-AtividadeRESUMO
In an effort to expand the spectrum of activity of the oxazolidinone class of antibacterial agents to include Gram-negative bacteria, a series of new carbon-carbon linked pyrazolylphenyl analogues has been prepared. The alpha-N-substituted methyl pyrazole (10alpha) in the C3-linked series exhibited very good Gram-positive activity with MICs Assuntos
Antibacterianos/química
, Antibacterianos/farmacologia
, Farmacorresistência Bacteriana
, Carbono/química
, Desenho de Fármacos
, Avaliação Pré-Clínica de Medicamentos
, Resistência a Múltiplos Medicamentos
, Bactérias Gram-Negativas/efeitos dos fármacos
, Bactérias Gram-Positivas/efeitos dos fármacos
, Haemophilus influenzae/efeitos dos fármacos
, Testes de Sensibilidade Microbiana
, Moraxella catarrhalis/efeitos dos fármacos
, Oxazóis
, Pirazóis
, Relação Estrutura-Atividade