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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.
PLoS One ; 14(2): e0211568, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30811418

RESUMO

Physical activity promotes metabolic and cardiovascular health benefits that derive in part from the transcriptional responses to exercise that occur within skeletal muscle and other organs. There is interest in discovering a pharmacologic exercise mimetic that could imbue wellness and alleviate disease burden. However, the molecular physiology by which exercise signals the transcriptional response is highly complex, making it challenging to identify a single target for pharmacological mimicry. The current studies evaluated the transcriptome responses in skeletal muscle, heart, liver, and white and brown adipose to novel small molecule activators of AMPK (pan-activators for all AMPK isoforms) compared to that of exercise. A striking level of congruence between exercise and pharmacological AMPK activation was observed across the induced transcriptome of these five tissues. However, differences in acute metabolic response between exercise and pharmacologic AMPK activation were observed, notably for acute glycogen balances and related to the energy expenditure induced by exercise but not pharmacologic AMPK activation. Nevertheless, intervention with repeated daily administration of short-acting activation of AMPK was found to mitigate hyperglycemia and hyperinsulinemia in four rodent models of metabolic disease and without the cardiac glycogen accretion noted with sustained pharmacologic AMPK activation. These findings affirm that activation of AMPK is a key node governing exercise mediated transcription and is an attractive target as an exercise mimetic.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Tecido Adiposo/metabolismo , Fígado/metabolismo , Músculo Esquelético/metabolismo , Miocárdio/metabolismo , Animais , Metabolismo Energético , Ativação Enzimática/efeitos dos fármacos , Ácidos Graxos/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Glucose/metabolismo , Homeostase , Camundongos Endogâmicos C57BL , Oxirredução , Condicionamento Físico Animal
4.
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
5.
Bioorg Med Chem Lett ; 22(22): 6811-6, 2012 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-22672801

RESUMO

Orally bioavailable inhibitors of ß-(1,3)-D-glucan synthase have been pursued as new, broad-spectrum fungicidal therapies suitable for treatment in immunocompromised patients. Toward this end, a collaborative medicinal chemistry program was established based on semisynthetic derivatization of the triterpenoid glycoside natural product enfumafungin in order to optimize in vivo antifungal activity and oral absorption properties. In the course of these studies, it was hypothesized that the pharmacokinetic properties of the semisynthetic enfumafungin analog 3 could be improved by tethering the alkyl groups proximal to the basic nitrogen of the C3-aminoether side chain into an azacyclic system, so as to preclude oxidative N-demethylation. The results of this research effort are disclosed herein.


Assuntos
Antifúngicos/síntese química , Inibidores Enzimáticos/síntese química , Glucosiltransferases/antagonistas & inibidores , Glicosídeos/química , Triterpenos/química , Administração Oral , Animais , Antifúngicos/química , Antifúngicos/farmacocinética , Candida albicans/efeitos dos fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Glucosiltransferases/metabolismo , Glicosídeos/síntese química , Glicosídeos/farmacocinética , Meia-Vida , Camundongos , Relação Estrutura-Atividade , Triterpenos/síntese química , Triterpenos/farmacocinética
6.
Maturitas ; 64(1): 46-51, 2009 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-19679413

RESUMO

OBJECTIVE: To test the role of ERbeta in the control of estrogen-dependent thermoregulation in rats. METHODS: Test the ability of an ERbeta-selective ligand to suppress the elevation in basal rat tail skin temperature (TST) caused by ovariectomy (OVX). RESULTS: ERbeta-19 is a tetrahydrofluorenone ERbeta-selective ligand that displaces 0.1 nM estradiol from ERbeta with an IC50 of 1.8 nM compared to an IC50 of 141 nM for ERalpha. Like estradiol, it acts as an agonist on ERbeta-mediated transactivation and transrepression with 25- and 60-fold selectivity, respectively, over ERalpha-controlled transcription. Administration of estradiol to estrogen-depleted rats suppresses the ovariectomy-induced elevation of TST. Similar treatment of OVX rats with ERbeta-19 also results in suppression of elevated TST. However, in contrast to estradiol, ERbeta-19 does not suppress body weight, does not increase uterine weight, nor does it stimulate uterocalin biomarker expression which is under the control of ERalpha. Thus, the ERbeta-19 suppression of rat TST is mediated by ERbeta without eliciting the activity of ERalpha. CONCLUSION: Estrogen-sensitive thermoregulation in ovariectomized rats can be controlled by an ERbeta-selective ligand.


Assuntos
Regulação da Temperatura Corporal/genética , Estradiol/farmacologia , Receptor beta de Estrogênio/agonistas , Fluorenos/farmacologia , Temperatura Cutânea/genética , Animais , Regulação da Temperatura Corporal/fisiologia , Peso Corporal/efeitos dos fármacos , Estradiol/genética , Estradiol/metabolismo , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/genética , Receptor beta de Estrogênio/metabolismo , Feminino , Regulação da Expressão Gênica , Ligantes , Lipocalinas/metabolismo , Tamanho do Órgão/efeitos dos fármacos , Ovariectomia , Ratos , Ratos Sprague-Dawley , Temperatura Cutânea/fisiologia , Cauda , Útero/metabolismo
7.
Bioorg Med Chem Lett ; 16(17): 4652-6, 2006 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-16777408

RESUMO

Several tetrahydrofluorenones with a triazole fused across C7-C8 showed high levels of ERbeta-selectivity and were found to be potent ERbeta-agonists. As a class they demonstrate improved oral bioavailability in the rat over a parent class of 7-hydroxy-tetrahydrofluorenones. The most selective agonist displayed 5.7 nM affinity and 333-fold selectivity for ERbeta.


Assuntos
Compostos Azo/síntese química , Compostos Azo/farmacologia , Receptor beta de Estrogênio/agonistas , Fluorenos/química , Fluorenos/farmacologia , Animais , Compostos Azo/química , Compostos Azo/farmacocinética , Receptor beta de Estrogênio/metabolismo , Fluorenos/síntese química , Fluorenos/farmacocinética , Humanos , Ligantes , Estrutura Molecular , Ratos , Relação Estrutura-Atividade
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