RESUMO
Serious infections caused by multidrug-resistant (MDR) organisms (Klebsiella pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumannii) present a critical need for innovative drug development. Herein, we describe the preclinical evaluation of YU253911, 2, a novel γ-lactam siderophore antibiotic with potent antimicrobial activity against MDR Gram-negative pathogens. Penicillin-binding protein (PBP) 3 was shown to be a target of 2 using a binding assay with purified P. aeruginosa PBP3. The specific binding interactions with P. aeruginosa were further characterized with a high-resolution (2.0 Å) X-ray structure of the compound's acylation product in P. aeruginosa PBP3. Compound 2 was shown to have a concentration >1 µg/ml at the 6 h time point when administered intravenously or subcutaneously in mice. Employing a meropenem resistant strain of P. aeruginosa, 2 was shown to have dose-dependent efficacy at 50 and 100 mg/kg q6h dosing in a mouse thigh infection model. Lastly, we showed that a novel γ-lactam and ß-lactamase inhibitor (BLI) combination can effectively lower minimum inhibitory concentrations (MICs) against carbapenem resistant Acinetobacter spp. that demonstrated decreased susceptibility to 2 alone.
Assuntos
Antibacterianos/farmacologia , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Klebsiella pneumoniae/efeitos dos fármacos , Lactamas/farmacologia , Sideróforos/farmacologia , Acinetobacter baumannii/efeitos dos fármacos , Antibacterianos/síntese química , Antibacterianos/química , Relação Dose-Resposta a Droga , Lactamas/síntese química , Lactamas/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Pseudomonas aeruginosa/efeitos dos fármacos , Sideróforos/síntese química , Sideróforos/química , Relação Estrutura-AtividadeRESUMO
Treatment of multidrug-resistant Gram-negative bacterial pathogens represents a critical clinical need. Here, we report a novel γ-lactam pyrazolidinone that targets penicillin-binding proteins (PBPs) and incorporates a siderophore moiety to facilitate uptake into the periplasm. The MIC values of γ-lactam YU253434, 1, are reported along with the finding that 1 is resistant to hydrolysis by all four classes of ß-lactamases. The druglike characteristics and mouse PK data are described along with the X-ray crystal structure of 1 binding to its target PBP3.
Assuntos
Antibacterianos/farmacologia , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Lactamas/química , Sideróforos/química , Animais , Antibacterianos/síntese química , Antibacterianos/metabolismo , Antibacterianos/farmacocinética , Proteínas de Bactérias/antagonistas & inibidores , Proteínas de Bactérias/metabolismo , Sítios de Ligação , Domínio Catalítico , Cristalografia por Raios X , Bactérias Gram-Negativas/efeitos dos fármacos , Meia-Vida , Lactamas/metabolismo , Lactamas/farmacocinética , Lactamas/farmacologia , Camundongos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Proteínas de Ligação às Penicilinas/antagonistas & inibidores , Proteínas de Ligação às Penicilinas/metabolismo , Pseudomonas aeruginosa/metabolismo , Sideróforos/metabolismoRESUMO
Through fragment-based drug design focused on engaging the active site of IRAK4 and leveraging three-dimensional topology in a ligand-efficient manner, a micromolar hit identified from a screen of a Pfizer fragment library was optimized to afford IRAK4 inhibitors with nanomolar potency in cellular assays. The medicinal chemistry effort featured the judicious placement of lipophilicity, informed by co-crystal structures with IRAK4 and optimization of ADME properties to deliver clinical candidate PF-06650833 (compound 40). This compound displays a 5-unit increase in lipophilic efficiency from the fragment hit, excellent kinase selectivity, and pharmacokinetic properties suitable for oral administration.
Assuntos
Descoberta de Drogas , Quinases Associadas a Receptores de Interleucina-1/antagonistas & inibidores , Isoquinolinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Administração Oral , Relação Dose-Resposta a Droga , Humanos , Quinases Associadas a Receptores de Interleucina-1/metabolismo , Isoquinolinas/administração & dosagem , Isoquinolinas/química , Lactamas , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/química , Relação Estrutura-AtividadeRESUMO
Sequential modification of the previously identified 4-[3-aryl-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ols led to the identification of a new series of 1-(2-morpholin-2-ylethyl)-3-aryl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxides that are potent and selective inhibitors of the norepinephrine transporter over both the serotonin and dopamine transporters. One representative compound 10b (WYE-114152) had low nanomolar hNET potency (IC(50) = 15 nM) and good selectivity for hNET over hSERT (>430-fold) and hDAT (>548-fold). 10b was additionally bioavailable following oral dosing and demonstrated efficacy in rat models of acute, inflammatory, and neuropathic pain.