RESUMO
A major determinant of maximal exercise capacity is the delivery of oxygen to exercising muscles. myo-Inositol trispyrophosphate (ITPP) is a recently identified membrane-permeant molecule that causes allosteric regulation of Hb oxygen binding affinity. In normal mice, i.p. administration of ITPP (0.5-3 g/kg) caused a dose-related increase in the oxygen tension at which Hb is 50% saturated (p50), with a maximal increase of 31%. In parallel experiments, ITPP caused a dose-related increase in maximal exercise capacity, with a maximal increase of 57 +/- 13% (P = 0.002). In transgenic mice with severe heart failure caused by cardiac-specific overexpression of G alpha q, i.p. ITPP increased exercise capacity, with a maximal increase of 63 +/- 7% (P = 0.005). Oral administration of ITPP in drinking water increased Hb p50 and maximal exercise capacity (+34 +/- 10%; P < 0.002) in normal and failing mice. Consistent with increased tissue oxygen availability, ITPP decreased hypoxia inducible factor-1alpha mRNA expression in myocardium. It had no effect on myocardial contractility in isolated mouse cardiac myocytes and did not affect arterial blood pressure in vivo in mice. Thus, ITPP decreases the oxygen binding affinity of Hb, increases tissue oxygen delivery, and increases maximal exercise capacity in normal mice and mice with severe heart failure. ITPP is thus an attractive candidate for the therapy of patients with reduced exercise capacity caused by heart failure.
Assuntos
Tolerância ao Exercício/efeitos dos fármacos , Insuficiência Cardíaca/tratamento farmacológico , Hemoglobinas/efeitos dos fármacos , Fosfatos de Inositol/farmacologia , Regulação Alostérica/efeitos dos fármacos , Animais , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/genética , Insuficiência Cardíaca/fisiopatologia , Hemoglobinas/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Fosfatos de Inositol/uso terapêutico , Camundongos , Camundongos Transgênicos , Oxigênio/metabolismo , RNA Mensageiro , Resultado do TratamentoRESUMO
Novel therapies are required to treat chronic bacterial infections in cystic fibrosis (CF) sufferers. The most common pathogen responsible for these infections is Pseudomonas aeruginosa, which persists within the lungs of CF sufferers despite intensive antibiotic treatment. P. aeruginosa elastase (also known as LasB or pseudolysin) is a key virulence determinant that contributes to the pathogenesis and persistence of P. aeruginosa infections in CF patients. The crucial role of LasB in pseudomonal virulence makes it a good target for the development of an adjuvant drug for CF treatment. Herein we discuss the discovery of a new series of LasB inhibitors by virtual screening and computer assisted drug design (CADD) and their optimization leading to compounds 29 and 39 (K i = 0.16 µM and 0.12 µM, respectively).
RESUMO
The diazabicyclooctanes (DBOs) are a class of serine ß-lactamase (SBL) inhibitors that use a strained urea moiety as the warhead to react with the active serine residue in the active site of SBLs. The first in-class drug, avibactam, as well as several other recently approved DBOs (e.g., relebactam) or those in clinical development (e.g., nacubactam and zidebactam) potentiate activity of ß-lactam antibiotics, to various extents, against carbapenem-resistant Enterobacterales (CRE) carrying class A, C, and D SBLs; however, none of these are able to rescue the activity of ß-lactam antibiotics against carbapenem-resistant Acinetobacter baumannii (CRAB), a WHO "critical priority pathogen" producing class D OXA-type SBLs. Herein, we describe the chemical optimization and resulting structure-activity relationship, leading to the discovery of a novel DBO, ANT3310, which uniquely has a fluorine atom replacing the carboxamide and stands apart from the current DBOs in restoring carbapenem activity against OXA-CRAB as well as SBL-carrying CRE pathogens.
Assuntos
Acinetobacter/efeitos dos fármacos , Antibacterianos/farmacologia , Enterobacteriaceae/efeitos dos fármacos , Octanos/química , beta-Lactamases/química , Animais , Antibacterianos/química , Antibacterianos/metabolismo , Sítios de Ligação , Carbapenêmicos/farmacologia , Avaliação Pré-Clínica de Medicamentos , Farmacorresistência Bacteriana/efeitos dos fármacos , Meia-Vida , Camundongos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Octanos/metabolismo , Octanos/farmacologia , Estereoisomerismo , Relação Estrutura-Atividade , Inibidores de beta-Lactamases/química , Inibidores de beta-Lactamases/metabolismo , Inibidores de beta-Lactamases/farmacologia , beta-Lactamases/metabolismoRESUMO
The clinical effectiveness of the important ß-lactam class of antibiotics is under threat by the emergence of resistance, mostly due to the production of acquired serine- (SBL) and metallo-ß-lactamase (MBL) enzymes. To address this resistance issue, multiple ß-lactam/ß-lactamase inhibitor combinations have been successfully introduced into the clinic over the past several decades. However, all of those combinations contain SBL inhibitors and, as yet, there are no MBL inhibitors in clinical use. Consequently, there exists an unaddressed yet growing healthcare problem due to the rise in recent years of highly resistant strains which produce New Delhi metallo (NDM)-type metallo-carbapenemases. Previously, we reported the characterization of an advanced MBL inhibitor lead compound, ANT431. Herein, we discuss the completion of a lead optimization campaign culminating in the discovery of the preclinical candidate ANT2681, a potent NDM inhibitor with strong potential for clinical development.
Assuntos
Enterobacteriaceae , Inibidores de beta-Lactamases , Antibacterianos/farmacologia , Meropeném/farmacologia , Monobactamas , Inibidores de beta-Lactamases/farmacologiaRESUMO
The clinical effectiveness of carbapenem antibiotics such as meropenem is becoming increasingly compromised by the spread of both metallo-ß-lactamase (MBL) and serine-ß-lactamase (SBL) enzymes on mobile genetic elements, stimulating research to find new ß-lactamase inhibitors to be used in conjunction with carbapenems and other ß-lactam antibiotics. Herein, we describe our initial exploration of a novel chemical series of metallo-ß-lactamase inhibitors, from concept to efficacy, in a survival model using an advanced tool compound (ANT431) in conjunction with meropenem.
Assuntos
Antibacterianos/farmacologia , Enterobacteriáceas Resistentes a Carbapenêmicos/efeitos dos fármacos , Farmacorresistência Bacteriana Múltipla , Infecções por Enterobacteriaceae/tratamento farmacológico , Inibidores de beta-Lactamases/química , Carbapenêmicos/farmacologia , Cristalografia por Raios X , Concentração Inibidora 50 , Meropeném/farmacologia , Testes de Sensibilidade Microbiana , Ácidos Picolínicos/química , Ácidos Picolínicos/farmacologia , Ligação Proteica , Relação Estrutura-Atividade , Inibidores de beta-Lactamases/farmacologia , beta-LactamasesRESUMO
The azide-based carbamate or carbonate protecting group (Azoc) shown above can be removed in less than 2 min under neutral conditions using trimethyl or tributyl phosphine as well as polymer-bound triphenyl phosphine. It was shown to be orthogonal to Fmoc and Mtt for peptide synthesis and to afford beta-glycoside with a 2-aminoglucosyl donor by virtue of the neighboring group participation.