RESUMO
A series of 2-amino-[1,8]-naphthyridine-3-carboxamides (ANCs) with potent inhibition of bacterial NAD(+)-dependent DNA ligases (LigAs) evolved from a 2,4-diaminopteridine derivative discovered by HTS. The design was guided by several highly resolved X-ray structures of our inhibitors in complex with either Streptococcus pneumoniae or Escherichia coli LigA. The structure-activity-relationship based on the ANC scaffold is discussed. The in-depth characterization of 2-amino-6-bromo-7-(trifluoromethyl)-[1,8]-naphthyridine-3-carboxamide, which displayed promising in vitro (MIC Staphylococcus aureus 1 mg/L) and in vivo anti-staphylococcal activity, is presented.
Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , DNA Ligases/antagonistas & inibidores , Desenho de Fármacos , Staphylococcus/efeitos dos fármacos , Animais , Antibacterianos/química , Antibacterianos/uso terapêutico , Cristalografia por Raios X , DNA Bacteriano/antagonistas & inibidores , Concentração Inibidora 50 , Camundongos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Ratos , Infecções Estafilocócicas/tratamento farmacológico , Relação Estrutura-AtividadeRESUMO
The discovery of a new series of piperidine-based renin inhibitors is described herein. SAR optimization upon the P3 renin sub-pocket is described, leading to the discovery of 9 and 41, two bioavailable renin inhibitors orally active at low doses in a transgenic rat model of hypertension.
Assuntos
Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Piperidinas/síntese química , Piperidinas/farmacologia , Renina/antagonistas & inibidores , Animais , Anti-Hipertensivos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Citocromo P-450 CYP3A , Inibidores das Enzimas do Citocromo P-450 , Desenho de Fármacos , Modelos Moleculares , Piperidinas/química , Conformação Proteica , Ratos , Relação Estrutura-Atividade , Difração de Raios XRESUMO
The optimization of the 4-position of recently described new 3,4-disubstituted piperidine-based renin inhibitors is reported herein. The synthesis and characterization of compounds leading to the discovery of 11 (ACT-178882, MK-1597), a renin inhibitor with a suitable profile for development is described.
Assuntos
Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Piperidinas/síntese química , Piperidinas/farmacologia , Renina/antagonistas & inibidores , Angiotensinogênio/genética , Animais , Animais Geneticamente Modificados , Citocromo P-450 CYP3A , Inibidores das Enzimas do Citocromo P-450 , Inibidores Enzimáticos/química , Humanos , Indicadores e Reagentes , Modelos Moleculares , Piperidinas/química , Ratos , Renina/genética , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
New classes of de novo designed renin inhibitors are reported. Some of these compounds display excellent in vitro and in vivo activities toward human renin in a TGR model. The synthesis of these new types of mono- and bicyclic scaffolds are reported, and properties of selected compounds discussed.
Assuntos
Compostos Bicíclicos com Pontes/classificação , Compostos Bicíclicos com Pontes/farmacologia , Inibidores Enzimáticos/classificação , Inibidores Enzimáticos/farmacologia , Renina/antagonistas & inibidores , Compostos Bicíclicos com Pontes/química , Cristalografia por Raios X , Desenho de Fármacos , Inibidores Enzimáticos/química , Humanos , Modelos Moleculares , Estrutura Molecular , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Our strategy to combat resistant bacteria consisted of targeting the GyrB/ParE ATP-binding sites located on bacterial DNA gyrase and topoisomerase IV and not utilized by marketed antibiotics. Screening around the minimal ethyl urea binding motif led to the identification of isoquinoline ethyl urea 13 as a promising starting point for fragment evolution. The optimization was guided by structure-based design and focused on antibacterial activity in vitro and in vivo, culminating in the discovery of unprecedented substituents able to interact with conserved residues within the ATP-binding site. A detailed characterization of the lead compound highlighted the potential for treatment of the problematic fluoroquinolone-resistant MRSA, VRE, and S. pneumoniae, and the possibility to offer patients an intravenous-to-oral switch therapy was supported by the identification of a suitable prodrug concept. Eventually, hERG K-channel block was identified as the main limitation of this chemical series, and efforts toward its minimization are reported.
Assuntos
Antibacterianos/farmacologia , Isoquinolinas/farmacologia , Animais , Antibacterianos/química , Área Sob a Curva , Descoberta de Drogas , Bactérias Gram-Negativas/efeitos dos fármacos , Meia-Vida , Ligação de Hidrogênio , Isoquinolinas/química , Isoquinolinas/farmacocinética , Isoquinolinas/uso terapêutico , Testes de Sensibilidade Microbiana , Canais de Potássio/efeitos dos fármacos , Ratos , Infecções Respiratórias/tratamento farmacológico , Infecções Respiratórias/microbiologia , Solubilidade , Ureia/químicaRESUMO
Starting from known piperidine renin inhibitors, a new series of 3,9-diazabicyclo[3.3.1]nonene derivatives was rationally designed and prepared. Optimization of the positions 3, 6, and 7 of the diazabicyclonene template led to potent renin inhibitors. The substituents attached at the positions 6 and 7 were essential for the binding affinity of these compounds for renin. The introduction of a substituent attached at the position 3 did not modify the binding affinity but allowed the modulation of the ADME properties. Our efforts led to the discovery of compound (+)-26g that inhibits renin with an IC(50) of 0.20 nM in buffer and 19 nM in plasma. The pharmacokinetics properties of this and other similar compounds are discussed. Compound (+)-26g is well absorbed in rats and efficacious at 10 mg/kg in vivo.
Assuntos
Compostos Azabicíclicos/síntese química , Compostos Azabicíclicos/farmacologia , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Renina/antagonistas & inibidores , Sítios de Ligação , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/química , Modelos Moleculares , Conformação Molecular , Relação Estrutura-AtividadeRESUMO
Two bis-trifluoromethyl pepstatin A analogues, carboxylic acid 1 and its methyl ester 2, have been synthesised in order to probe the properties and size of the trifluoromethyl (Tfm) group and compare it to the "bigger" isobutyl that is present in pepstatin A. The results demonstrate that Tfm can effectively replace the isobutyl chain as far as inhibitory activity against plasmepsin II (PM II), an aspartic proteinase from Plasmodium falciparum, is concerned. On the other hand, replacement of isobutyl by Tfm selectively affected activity against other aspartic proteinases tested. Two lines of evidence led to these conclusions. Firstly, compounds 1 and 2 retained single-digit nanomolar inhibitory activity against PM II, but were markedly less active against PM IV, cathepsin D and cathepsin E. Secondly, the X-ray crystal structures of the three complexes of PM II with 1, 2 and pepstatin A were obtained at 2.8, 2.4 and 1.7 A resolution, respectively. High overall similarity among the three complexes indicated that the central Tfm was well accommodated in the lipophilic S1 pocket of PM II, where it was involved in tight hydrophobic contacts. The interaction of PM II with Phe111 appeared to be crucial. Comparison of the crystal structures presented here, with X-ray structures or structural models of PM IV and cathepsin D, allowed an interpretation of the inhibition profiles of pepstatin A and its Tfm variants against these three enzymes. Interactions of the P1 side chain with amino acids that point into the S1 pocket appear to be critical for inhibitory activity. In summary, Tfm can be used to replace an isobutyl group and can affect the selectivity profile of a compound. These findings have implications for the design of novel bioactive molecules and synthetic mimics of natural compounds.
Assuntos
Antiparasitários/química , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Pepstatinas/química , Inibidores de Proteases/química , Animais , Antiparasitários/síntese química , Antiparasitários/farmacologia , Ácido Aspártico Endopeptidases/química , Catepsina D/antagonistas & inibidores , Catepsina D/química , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos , Humanos , Técnicas In Vitro , Modelos Moleculares , Conformação Molecular , Pepstatinas/síntese química , Pepstatinas/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/enzimologia , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Relação Estrutura-AtividadeRESUMO
In order to overcome the problem of drug resistance in malaria, it appears wise to concentrate drug discovery efforts toward new structural classes and new mechanisms of action. We report our results, targeting Plasmepsin II, a Plasmodium falciparum aspartic protease active in hemoglobin degradation, a parasite specific catabolic pathway. The results show that the new structural class is not only inhibiting PMII in vitro but is also active in a P. falciparum infected human red blood cell assay.
Assuntos
Antimaláricos/síntese química , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Plasmodium falciparum/efeitos dos fármacos , Animais , Antimaláricos/farmacologia , Avaliação Pré-Clínica de Medicamentos , Resistência a Medicamentos , Inibidores Enzimáticos/farmacologia , Proteínas de Protozoários , Relação Estrutura-AtividadeRESUMO
The malaria parasite Plasmodium falciparum degrades host cell hemoglobin inside an acidic food vacuole during the blood stage of the infectious cycle. A number of aspartic proteinases called plasmepsins (PMs) have been identified to play important roles in this degradation process and therefore generated significant interest as new antimalarial targets. Several x-ray structures of PMII have been described previously, but thus far, structure-guided drug design has been hampered by the fact that only inhibitors comprising a statine moiety or derivatives thereof have been published. Our drug discovery efforts to find innovative, cheap, and easily synthesized inhibitors against aspartic proteinases yielded some highly potent non-peptidic achiral inhibitors. A highly resolved (1.6 A) x-ray structure of PMII is presented, featuring a potent achiral inhibitor in an unprecedented orientation, contacting the catalytic aspartates indirectly via the "catalytic" water. Major side chain rearrangements in the active site occur, which open up a new pocket and allow a new binding mode of the inhibitor. Moreover, a second inhibitor molecule could be located unambiguously in the active site of PMII. These newly obtained structural insights will further guide our attempts to improve compound properties eventually leading to the identification of molecules suitable as antimalarial drugs.