Design and discovery of a selective small molecule κ opioid antagonist (2-methyl-N-((2'-(pyrrolidin-1-ylsulfonyl)biphenyl-4-yl)methyl)propan-1-amine, PF-4455242).
J Med Chem
; 54(16): 5868-77, 2011 Aug 25.
Article
em En
| MEDLINE
| ID: mdl-21744827
ABSTRACT
By use of parallel chemistry coupled with physicochemical property design, a series of selective κ opioid antagonists have been discovered. The parallel chemistry strategy utilized key monomer building blocks to rapidly expand the desired SAR space. The potency and selectivity of the in vitro κ antagonism were confirmed in the tail-flick analgesia model. This model was used to build an exposure-response relationship between the κ K(i) and the free brain drug levels. This strategy identified 2-methyl-N-((2'-(pyrrolidin-1-ylsulfonyl)biphenyl-4-yl)methyl)propan-1-amine, PF-4455242, which entered phase 1 clinical testing and has demonstrated target engagement in healthy volunteers.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Sulfonamidas
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Compostos de Bifenilo
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Desenho de Fármacos
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Receptores Opioides kappa
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Descoberta de Drogas
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Antagonistas de Entorpecentes
Tipo de estudo:
Prognostic_studies
Idioma:
En
Ano de publicação:
2011
Tipo de documento:
Article