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1.
Commun Biol ; 2: 271, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31372510

RESUMO

Dysregulation of the kynurenine pathway (KP) leads to imbalances in neuroactive metabolites associated with the pathogenesis of several neurodegenerative disorders, including Huntington's disease (HD). Inhibition of the enzyme kynurenine 3-monooxygenase (KMO) in the KP normalises these metabolic imbalances and ameliorates neurodegeneration and related phenotypes in several neurodegenerative disease models. KMO is thus a promising candidate drug target for these disorders, but known inhibitors are not brain permeable. Here, 19 new KMO inhibitors have been identified. One of these (1) is neuroprotective in a Drosophila HD model but is minimally brain penetrant in mice. The prodrug variant (1b) crosses the blood-brain barrier, releases 1 in the brain, thereby lowering levels of 3-hydroxykynurenine, a toxic KP metabolite linked to neurodegeneration. Prodrug 1b will advance development of targeted therapies against multiple neurodegenerative and neuroinflammatory diseases in which KP likely plays a role, including HD, Alzheimer's disease, and Parkinson's disease.


Assuntos
Encéfalo/efeitos dos fármacos , Quinurenina 3-Mono-Oxigenase/metabolismo , Doenças Neurodegenerativas/metabolismo , Animais , Barreira Hematoencefálica , Encéfalo/metabolismo , Inibidores Enzimáticos/farmacologia , Peróxido de Hidrogênio/metabolismo , Quinurenina 3-Mono-Oxigenase/antagonistas & inibidores , Camundongos , Doenças Neurodegenerativas/enzimologia
2.
ACS Med Chem Lett ; 3(7): 570-3, 2012 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-24900512

RESUMO

Triage of a set of antimalaria hit compounds, identified through high throughput screening against the Chloroquine sensitive (3D7) and resistant (Dd2) parasite Plasmodium falciparum strains identified several novel chemotypes suitable for hit-to-lead chemistry investigation. The set was further refined through investigation of their in vitro ADME properties, which identified templates with good potential to be developed further as antimalarial agents. One example was profiled in an in vivo murine Plasmodium berghei model of malaria infection.

3.
Bioorg Med Chem Lett ; 20(19): 5803-6, 2010 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-20732811

RESUMO

Following the discovery of 4-(substituted amino)-1-alkyl-pyrazolo[3,4-b]pyridine-5-carboxamides as potent and selective phosphodiesterase 4B inhibitors, [Hamblin, J. N.; Angell, T.; Ballentine, S., et al. Bioorg. Med. Chem. Lett.2008, 18, 4237] the SAR of the 5-position was investigated further. A range of substituted heterocycles showed good potencies against PDE4. Optimisation using X-ray crystallography and computational modelling led to the discovery of 16, with sub-nM inhibition of LPS-induced TNF-α production from isolated human peripheral blood mononuclear cells.


Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/química , Compostos Heterocíclicos/química , Inibidores de Fosfodiesterase/química , Pirazóis/química , Piridinas/química , Sítios de Ligação , Simulação por Computador , Cristalografia por Raios X , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Humanos , Modelos Químicos , Modelos Moleculares , Inibidores de Fosfodiesterase/síntese química , Inibidores de Fosfodiesterase/farmacologia , Estrutura Terciária de Proteína , Pirazóis/síntese química , Pirazóis/farmacologia , Piridinas/síntese química , Piridinas/farmacologia , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/metabolismo
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