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1.
Bioorg Med Chem ; 69: 116812, 2022 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-35772287

RESUMO

A therapeutic approach that holds the potential to treat all Duchenne muscular dystrophy (DMD) patient populations is utrophin modulation. Ezutromid, a first generation utrophin modulator which was later found to act via antagonism of the arylhydrocarbon receptor, progressed to Phase 2 clinical trials. Although interim data showed target engagement and functional improvements, ezutromid ultimately failed to meet its clinical endpoints. We recently described the identification of a new class of hydrazide utrophin modulators which has a different mechanism of action to ezutromid. In this study we report our early optimisation studies on this hydrazide series. The new analogues had significantly improved potency in cell-based assays, increased sp3 character and reduced lipophilicity, which also improved their physicochemical properties. A representative new analogue combining these attributes increased utrophin protein in dystrophic mouse cells showing it can be used as a chemical tool to reveal new insights regarding utrophin upregulation as a strategy for DMD therapeutic intervention.


Assuntos
Distrofia Muscular de Duchenne , Animais , Hidrazinas/farmacologia , Hidrazinas/uso terapêutico , Camundongos , Músculo Esquelético/metabolismo , Distrofia Muscular de Duchenne/tratamento farmacológico , Distrofia Muscular de Duchenne/metabolismo , Relação Estrutura-Atividade , Regulação para Cima , Utrofina/genética , Utrofina/metabolismo , Utrofina/uso terapêutico
2.
ACS Med Chem Lett ; 11(12): 2421-2427, 2020 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-33335663

RESUMO

Utrophin modulation is a disease-modifying therapeutic strategy for Duchenne muscular dystrophy that would be applicable to all patient populations. To improve the suboptimal profile of ezutromid, the first-in-class clinical candidate, a second generation of utrophin modulators bearing a phosphinate ester moiety was developed. This modification significantly improved the physicochemical and ADME properties, but one of the main lead molecules was found to have dose-limiting hepatotoxicity. In this work we describe how less lipophilic analogues retained utrophin modulatory activity in a reporter gene assay, upregulated utrophin protein in dystrophic mouse muscle cells, but also had improved physicochemical and ADME properties. Notably, ClogP was found to directly correlate with pIC50 in HepG2 cells, hence leading to a potentially safer toxicological profiles in this series. Compound 21 showed a balanced profile (H2K EC50: 4.17 µM, solubility: 477 µM, mouse hepatocyte T 1/2 > 240 min) and increased utrophin protein 1.6-fold in a Western blot assay.

3.
Tetrahedron ; 76(2): 130819, 2020 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-32713969

RESUMO

Following on from ezutromid, the first-in-class benzoxazole utrophin modulator that progressed to Phase 2 clinical trials for the treatment of Duchenne muscular dystrophy, a new chemotype was designed to optimise its physicochemical and ADME profile. Herein we report the synthesis of SMT022357, a second generation utrophin modulator preclinical candidate, and an asymmetric synthesis of its constituent enantiomers. The pharmacological properties of both enantiomers were evaluated in vitro and in vivo. No significant difference in the activity or efficacy was observed between the two enantiomers; activity was found to be comparable to the racemic mixture.

4.
J Med Chem ; 63(14): 7880-7891, 2020 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-32551645

RESUMO

Utrophin modulation is a promising therapeutic strategy for Duchenne muscular dystrophy (DMD), which should be applicable to all patient populations. Following on from ezutromid, the first-generation utrophin modulator, we describe the development of a second generation of utrophin modulators, based on the bioisosteric replacement of the sulfone group with a phosphinate ester and substitution of the metabolically labile naphthalene with a haloaryl substituent. The improved physicochemical and absorption, distribution, metabolism, and excretion (ADME) properties, further reflected in the enhanced pharmacokinetic profile of the most advanced compounds, 30 and 27, led to significantly better in vivo exposure compared to ezutromid and alleviation of the dystrophic phenotype in mdx mice. While 30 was found to have dose-limiting hepatotoxicity, 27 and its enantiomers exhibited limited off-target effects, resulting in a safe profile and highlighting their potential utility as next-generation utrophin modulators suitable for progression toward a future DMD therapy.


Assuntos
Benzoxazóis/uso terapêutico , Distrofia Muscular de Duchenne/tratamento farmacológico , Utrofina/metabolismo , Animais , Benzoxazóis/síntese química , Benzoxazóis/farmacocinética , Benzoxazóis/toxicidade , Escherichia coli/efeitos dos fármacos , Camundongos Endogâmicos mdx , Estrutura Molecular , Distrofia Muscular de Duchenne/metabolismo , Testes de Mutagenicidade , Ratos , Salmonella typhimurium/efeitos dos fármacos , Estereoisomerismo , Relação Estrutura-Atividade , Regulação para Cima/efeitos dos fármacos
5.
J Med Chem ; 63(5): 2547-2556, 2020 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-31599580

RESUMO

5-(Ethylsulfonyl)-2-(naphthalen-2-yl)benzo[d]oxazole (ezutromid, 1) is a first-in-class utrophin modulator that has been evaluated in a phase 2 clinical study for the treatment of Duchenne muscular dystrophy (DMD). Ezutromid was found to undergo hepatic oxidation of its 2-naphthyl substituent to produce two regioisomeric 1,2-dihydronaphthalene-1,2-diols, DHD1 and DHD3, as the major metabolites after oral administration in humans and rodents. In many patients, plasma levels of the DHD metabolites were found to exceed those of ezutromid. Herein, we describe the structural elucidation of the main metabolites of ezutromid, the regio- and relative stereochemical assignments of DHD1 and DHD3, their de novo chemical synthesis, and their production in systems in vitro. We further elucidate the likely metabolic pathway and CYP isoforms responsible for DHD1 and DHD3 production and characterize their physicochemical, ADME, and pharmacological properties and their preliminary toxicological profiles.


Assuntos
Benzoxazóis/metabolismo , Distrofia Muscular de Duchenne/tratamento farmacológico , Naftalenos/metabolismo , Naftóis/metabolismo , Utrofina/metabolismo , Animais , Hidrocarboneto de Aril Hidroxilases/metabolismo , Benzoxazóis/efeitos adversos , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Redes e Vias Metabólicas , Metaboloma , Camundongos , Distrofia Muscular de Duchenne/metabolismo , Naftalenos/efeitos adversos , Naftóis/efeitos adversos , Naftóis/análise , Naftóis/síntese química , Ratos , Estereoisomerismo
6.
J Am Chem Soc ; 139(24): 8267-8276, 2017 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-28548849

RESUMO

Molecules labeled with fluorine-18 (18F) are used in positron emission tomography to visualize, characterize and measure biological processes in the body. Despite recent advances in the incorporation of 18F onto arenes, the development of general and efficient approaches to label radioligands necessary for drug discovery programs remains a significant task. This full account describes a derisking approach toward the radiosynthesis of heterocyclic positron emission tomography (PET) radioligands using the copper-mediated 18F-fluorination of aryl boron reagents with 18F-fluoride as a model reaction. This approach is based on a study examining how the presence of heterocycles commonly used in drug development affects the efficiency of 18F-fluorination for a representative aryl boron reagent, and on the labeling of more than 50 (hetero)aryl boronic esters. This set of data allows for the application of this derisking strategy to the successful radiosynthesis of seven structurally complex pharmaceutically relevant heterocycle-containing molecules.

7.
Org Lett ; 16(22): 6004-7, 2014 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-25379614

RESUMO

Arenes substituted with perfluoroalkyl groups are attractive targets for drug and agrochemical development. Exploiting the carbenic character of donor/acceptor diazo compounds, a diversity-oriented synthesis of perfluoroalkylated arenes, for late stage fluorofunctionalization, is described. The reaction of 1-(diazo-2,2,2-trifluoroethyl)arenes with HF, F/Br, F2, CF3H, and CF3SH sources give direct access to a variety of perfluoroalkyl-substituted arenes presenting with incremental fluorine content. The value of this approach is also demonstrated for radiochemistry and positron emission tomography with the [(18)F]-labeling of CF3CHF-, CF3CBrF-, and CF3CF2-arenes from [(18)F]fluoride.


Assuntos
Compostos Azo/química , Hidrocarbonetos Fluorados/síntese química , Radioisótopos de Flúor/química , Hidrocarbonetos Bromados/química , Hidrocarbonetos Fluorados/química , Estrutura Molecular , Tomografia por Emissão de Pósitrons
8.
Angew Chem Int Ed Engl ; 53(16): 4181-5, 2014 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-24644083

RESUMO

This paper describes the hydrofluorination of alkenes through sequential H(-) and F(+) addition under palladium catalysis. The reaction is cis specific, thus providing access to benzylic fluorides. The mechanism of this reaction involves an ionic pathway and is distinct from known hydrofluorinations involving radical intermediates. The first catalytic enantioselective hydrofluorination is also disclosed.

9.
Chem Commun (Camb) ; 48(30): 3614-6, 2012 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-22396955

RESUMO

We herein present a general enamine-mediated α-alkylation of α-substituted aldehydes with carbenium ions for the stereoselective construction of quaternary stereogenic centers.

11.
Molecules ; 16(6): 5298-314, 2011 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-21701439

RESUMO

In this report, we have presented the first diastereoselective addition of phenylacetylene to chiral racemic chloroketones. The addition is controlled by the reactivity of the chloroketones that allowed the stereoselective reaction to be performed at -20 °C. Chiral racemic chloroketones are used in the reaction. By carefully controlling the temperature and the reaction time we were able to isolate the corresponding products in moderate yields and with good, simple and predictable facial stereoselection. Our reaction is a rare example of the use of chiral ketones in an enantioselective alkynylation reaction and opens new perspectives for the formation of chiral quaternary stereocenters.


Assuntos
Acetileno/análogos & derivados , Cetonas/química , Acetileno/química , Catálise , Ligantes , Ressonância Magnética Nuclear Biomolecular , Fenômenos de Química Orgânica , Estereoisomerismo
13.
Angew Chem Int Ed Engl ; 50(17): 3847-9, 2011 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-21448867
14.
Org Biomol Chem ; 8(18): 4117-23, 2010 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-20625608

RESUMO

We applied Horse Liver Alcohol Dehydrogenase (HLADH) to the enantioselective synthesis of six (2S)-2-arylpropanols, useful intermediates in the synthesis of Profens. The influence of substrate structure and reaction conditions on yields and enantioselectivity were investigated. The high yields and high enantioselectivity towards the (S)-enantiomer obtained in the bioreduction of 2-arylpropionic aldehydes, clearly indicate the achievement of a DKR process through a combination of an enzyme-catalyzed kinetic reduction with a chemical base-catalyzed racemization of the unreacted aldehydes. The racemization step is represented by the keto-enol equilibrium of the aldehyde and can be controlled by modulating pH and reaction conditions.


Assuntos
Álcool Desidrogenase/metabolismo , Aldeídos/química , Fígado/enzimologia , Propanóis/química , Propanóis/síntese química , Álcool Desidrogenase/química , Animais , Biocatálise , Cavalos , Concentração de Íons de Hidrogênio , Cinética , Estrutura Molecular , Estereoisomerismo
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