Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 6 de 6
Filtrar
Mais filtros

Base de dados
Tipo de documento
Intervalo de ano de publicação
1.
Bioorg Med Chem Lett ; 32: 127661, 2021 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-33160023

RESUMO

We previously reported medicinal chemistry efforts that identified MK-5204, an orally efficacious ß-1,3-glucan synthesis inhibitor derived from the natural product enfumafungin. Further extensive optimization of the C2 triazole substituent identified 4-pyridyl as the preferred replacement for the carboxamide of MK-5204, leading to improvements in antifungal activity in the presence of serum, and increased oral exposure. Reoptimizing the aminoether at C3 in the presence of this newly discovered C2 substituent, confirmed that the (R) t-butyl, methyl aminoether of MK-5204 provided the best balance of these two key parameters, culminating in the discovery of ibrexafungerp, which is currently in phase III clinical trials. Ibrexafungerp displayed significantly improved oral efficacy in murine infection models, making it a superior candidate for clinical development as an oral treatment for Candida and Aspergillus infections.


Assuntos
Antifúngicos/farmacologia , Aspergillus/efeitos dos fármacos , Candida albicans/efeitos dos fármacos , Glicosídeos/química , Triterpenos/química , beta-Glucanas/metabolismo , Administração Oral , Animais , Antifúngicos/síntese química , Antifúngicos/farmacocinética , Antifúngicos/uso terapêutico , Aspergilose/tratamento farmacológico , Candidíase/tratamento farmacológico , Modelos Animais de Doenças , Glicosídeos/farmacocinética , Glicosídeos/farmacologia , Glicosídeos/uso terapêutico , Meia-Vida , Camundongos , Relação Estrutura-Atividade , Triterpenos/farmacocinética , Triterpenos/farmacologia , Triterpenos/uso terapêutico
2.
Bioorg Med Chem Lett ; 30(17): 127357, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32738971

RESUMO

Our previously reported efforts to produce an orally active ß-1,3-glucan synthesis inhibitor through the semi-synthetic modification of enfumafungin focused on replacing the C2 acetoxy moiety with an aminotetrazole and the C3 glycoside with a N,N-dimethylaminoether moiety. This work details further optimization of the C2 heterocyclic substituent, which identified 3-carboxamide-1,2,4-triazole as a replacement for the aminotetrazole with comparable antifungal activity. Alkylation of either the carboxamidetriazole at C2 or the aminoether at C3 failed to significantly improve oral efficacy. However, replacement of the isopropyl alpha amino substituent with a t-butyl, improved oral exposure while maintaining antifungal activity. These two structural modifications produced MK-5204, which demonstrated broad spectrum activity against Candida species and robust oral efficacy in a murine model of disseminated Candidiasis without the N-dealkylation liability observed for the previous lead.


Assuntos
Antifúngicos/química , Triazóis/química , beta-Glucanas/metabolismo , Administração Oral , Animais , Antifúngicos/metabolismo , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Candida/efeitos dos fármacos , Candidíase/tratamento farmacológico , Modelos Animais de Doenças , Glucosiltransferases/antagonistas & inibidores , Glucosiltransferases/metabolismo , Glicosídeos/química , Meia-Vida , Camundongos , Testes de Sensibilidade Microbiana , Estereoisomerismo , Relação Estrutura-Atividade , Triazóis/metabolismo , Triazóis/farmacologia , Triazóis/uso terapêutico , Triterpenos/química , beta-Glucanas/química
3.
Bioorg Med Chem Lett ; 25(24): 5813-8, 2015 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-26542966

RESUMO

The clinical success of the echinocandins, which can only be administered parentally, has validated ß-1,3-glucan synthase (GS) as an antifungal target. Semi-synthetic modification of enfumafungin, a triterpene glycoside natural product, was performed with the aim of producing a new class of orally active GS inhibitors. Replacement of the C2 acetoxy moiety with various heterocycles did not improve GS or antifungal potency. However, replacement of the C3 glycoside with an aminoether moiety dramatically improved oral pharmacokinetic (PK) properties while maintaining GS and antifungal potency. Installing an aminotetrazole at C2 in conjunction with an N-alkylated aminoether at C3 produced derivatives with significantly improved GS and antifungal potency that exhibited robust oral efficacy in a murine model of disseminated candidiasis.


Assuntos
Antifúngicos/química , Glicosídeos/química , Triterpenos/química , beta-Glucanas/química , Administração Oral , Animais , Antifúngicos/farmacocinética , Antifúngicos/uso terapêutico , Aspergillus fumigatus/efeitos dos fármacos , Candida albicans/efeitos dos fármacos , Candidíase/tratamento farmacológico , Candidíase/veterinária , Glucosiltransferases/antagonistas & inibidores , Glucosiltransferases/metabolismo , Meia-Vida , Camundongos , Testes de Sensibilidade Microbiana , Relação Estrutura-Atividade , Terpenos/química , beta-Glucanas/farmacocinética , beta-Glucanas/uso terapêutico
4.
Proc Natl Acad Sci U S A ; 108(13): 5378-83, 2011 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-21389266

RESUMO

Platensimycin (PTM) is a recently discovered broad-spectrum antibiotic produced by Streptomyces platensis. It acts by selectively inhibiting the elongation-condensing enzyme FabF of the fatty acid biosynthesis pathway in bacteria. We report here that PTM is also a potent and highly selective inhibitor of mammalian fatty acid synthase. In contrast to two agents, C75 and cerulenin, that are widely used as inhibitors of mammalian fatty acid synthase, platensimycin specifically inhibits fatty acid synthesis but not sterol synthesis in rat primary hepatocytes. PTM preferentially concentrates in liver when administered orally to mice and potently inhibits hepatic de novo lipogenesis, reduces fatty acid oxidation, and increases glucose oxidation. Chronic administration of platensimycin led to a net reduction in liver triglyceride levels and improved insulin sensitivity in db/+ mice fed a high-fructose diet. PTM also reduced ambient glucose levels in db/db mice. These results provide pharmacological proof of concept of inhibiting fatty acid synthase for the treatment of diabetes and related metabolic disorders in animal models.


Assuntos
Adamantano/uso terapêutico , Aminobenzoatos/uso terapêutico , Anilidas/uso terapêutico , Diabetes Mellitus/tratamento farmacológico , Ácido Graxo Sintases/antagonistas & inibidores , Fígado Gorduroso/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Animais , Anti-Infecciosos/uso terapêutico , Modelos Animais de Doenças , Ácidos Graxos/biossíntese , Glucose/metabolismo , Humanos , Fígado/metabolismo , Camundongos , Camundongos Mutantes , Oxirredução , Esteróis/biossíntese
5.
ACS Med Chem Lett ; 8(1): 96-101, 2017 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-28105282

RESUMO

GPR120 (FFAR4) is a fatty acid sensing G protein coupled receptor (GPCR) that has been identified as a target for possible treatment of type 2 diabetes. A selective activator of GPR120 containing a chromane scaffold has been designed, synthesized, and evaluated in vivo. Results of these efforts suggest that chromane propionic acid 18 is a suitable tool molecule for further animal studies. Compound 18 is selective over the closely related target GPR40 (FFAR1), has a clean off-target profile, demonstrates suitable pharmacokinetic properties, and has been evaluated in wild-type/knockout GPR120 mouse oGTT studies.

6.
Chem Biol ; 22(10): 1362-73, 2015 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-26456734

RESUMO

Resistance to existing classes of antibiotics drives the need for discovery of novel compounds with unique mechanisms of action. Nargenicin A1, a natural product with limited antibacterial spectrum, was rediscovered in a whole-cell antisense assay. Macromolecular labeling in both Staphylococcus aureus and an Escherichia coli tolC efflux mutant revealed selective inhibition of DNA replication not due to gyrase or topoisomerase IV inhibition. S. aureus nargenicin-resistant mutants were selected at a frequency of ∼1 × 10(-9), and whole-genome resequencing found a single base-pair change in the dnaE gene, a homolog of the E. coli holoenzyme α subunit. A DnaE single-enzyme assay was exquisitely sensitive to inhibition by nargenicin, and other in vitro characterization studies corroborated DnaE as the target. Medicinal chemistry efforts may expand the spectrum of this novel mechanism antibiotic.


Assuntos
DNA Polimerase III/genética , Descoberta de Drogas , Antibacterianos/química , Antibacterianos/metabolismo , Antibacterianos/farmacologia , Replicação do DNA/efeitos dos fármacos , DNA Polimerase Dirigida por DNA/metabolismo , Farmacorresistência Bacteriana/genética , Escherichia coli/efeitos dos fármacos , Concentração Inibidora 50 , Lactonas/química , Lactonas/metabolismo , Lactonas/farmacologia , Mutação , Inibidores da Síntese de Ácido Nucleico/química , Inibidores da Síntese de Ácido Nucleico/farmacologia , Staphylococcus aureus/efeitos dos fármacos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA