Discovery of sulfonyl hydrazone derivative as a new selective PDE4A and PDE4D inhibitor by lead-optimization approach on the prototype LASSBio-448: In vitro and in vivo preclinical studies.
Eur J Med Chem
; 204: 112492, 2020 Oct 15.
Article
em En
| MEDLINE
| ID: mdl-32717478
ABSTRACT
Phosphodiesterase 4 (PDE4) inhibitors have emerged as a new strategy to treat asthma and other lung inflammatory diseases. Searching for new PDE4 inhibitors, we previously reported the discover of LASSBio-448, a sulfonamide with potential to prevent and reverse pivotal pathological features of asthma. In this paper, two novel series of sulfonamide (6a-6m) and sulfonyl hydrazone (7a-7j) analogues of LASSBio-448 have been synthetized and evaluated for selective inhibitory activity toward cAMP-specific PDE4 isoforms. From these studies, we have identified 7j (LASSBio-1632) as a new anti-asthmatic lead-candidate associated with selective inhibition of PDE4A and PDE4D isoenzymes and blockade of airway hyper-reactivity (AHR) and TNF-α production in the lung tissue. In addition, it was able to relax guinea pig trachea on non-sensitized and sensitized animals and showed great TGI permeability.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Desenho de Fármacos
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Inibidores Enzimáticos
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Nucleotídeo Cíclico Fosfodiesterase do Tipo 4
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Hidrazonas
Limite:
Animals
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Humans
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Male
Idioma:
En
Revista:
Eur J Med Chem
Ano de publicação:
2020
Tipo de documento:
Article