Discovery of MK-0952, a selective PDE4 inhibitor for the treatment of long-term memory loss and mild cognitive impairment.
Bioorg Med Chem Lett
; 20(22): 6387-93, 2010 Nov 15.
Article
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| MEDLINE
| ID: mdl-20933411
ABSTRACT
The structure-activity relationship of a novel series of 8-biarylnaphthyridinones acting as type 4 phosphodiesterase (PDE4) inhibitors for the treatment of long-term memory loss and mild cognitive impairment is described herein. The manuscript describes a new paradigm for the development of PDE4 inhibitor targeting CNS indications. This effort led to the discovery of the clinical candidate MK-0952, an intrinsically potent inhibitor (IC(50)=0.6 nM) displaying limited whole blood activity (IC(50)=555 nM). Supporting in vivo results in two preclinical efficacy tests and one test assessing adverse effects are also reported. The comparative profiles of MK-0952 and two other Merck compounds are described to validate the proposed hypothesis.
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1
Bases de datos:
MEDLINE
Asunto principal:
Inhibidores de Fosfodiesterasa
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Trastornos del Conocimiento
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Ciclopropanos
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Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4
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Memoria a Largo Plazo
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Compuestos Heterocíclicos con 2 Anillos
Límite:
Animals
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Female
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Humans
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Male
Idioma:
En
Revista:
Bioorg Med Chem Lett
Asunto de la revista:
BIOQUIMICA
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QUIMICA
Año:
2010
Tipo del documento:
Article