Isoform selective PLD inhibition by novel, chiral 2,8-diazaspiro[4.5]decan-1-one derivatives.
Bioorg Med Chem Lett
; 28(23-24): 3670-3673, 2018 12 15.
Article
em En
| MEDLINE
| ID: mdl-30528979
ABSTRACT
This letter describes the on-going SAR efforts to develop PLD1, PLD2 and dual PLD1/2 inhibitors with improved physiochemical and disposition properties as well as securing intellectual property position. Previous PLD inhibitors, based on a triazaspiro[4.5]decanone core proved to be highly selective PLD2 inhibitors, but with low plasma free fraction (rat, human fuâ¯<â¯0.03), high predicted hepatic clearance (rat CLhepâ¯>â¯65â¯mL/min/kg) and very short half-lives in vivo (t1/2â¯<â¯0.15â¯h). Removal of a nitrogen atom from this core generated a 2,8-diazaspiro[4.5]decanone core, harboring a new chiral center, as well as increased sp3 character. This new core demonstrated enantioselective inhibition of the individual PLD isoforms, enhanced free fraction (rat, human fuâ¯<â¯0.13), engendered moderate predicted hepatic clearance (rat CLhepâ¯â¼â¯43â¯mL/min/kg), improved half-lives in vivo (t1/2â¯>â¯3â¯h), and led to the first issued US patent claiming composition of matter for small molecule PLD inhibitors.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fosfolipase D
/
Compostos de Espiro
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Inibidores Enzimáticos
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article