Synthesis and evaluation of 4,6-disubstituted pyrimidines as CNS penetrant pan-muscarinic antagonists with a novel chemotype.
Bioorg Med Chem Lett
; 27(11): 2479-2483, 2017 06 01.
Article
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| MEDLINE
| ID: mdl-28427812
ABSTRACT
This letter describes the synthesis and structure activity relationship (SAR) studies of structurally novel M4 antagonists, based on a 4,6-disubstituted core, identified from a high-throughput screening campaign. A multi-dimensional optimization effort enhanced potency at both human and rat M4 (IC50s<300nM), with no substantial species differences noted. Moreover, CNS penetration proved attractive for this series (brainplasma Kp,uu=0.87), while other DMPK attributes were addressed in the course of the optimization effort, providing low in vivo clearance in rat (CLp=5.37mL/min/kg). Surprisingly, this series displayed pan-muscarinic antagonist activity across M1-5, despite the absence of the prototypical basic or quaternary amine moiety, thus offering a new chemotype from which to develop a next generation of pan-muscarinic antagonist agents.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Pirimidinas
/
Antagonistas Muscarínicos
/
Receptor Muscarínico M4
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Bioorg Med Chem Lett
Asunto de la revista:
BIOQUIMICA
/
QUIMICA
Año:
2017
Tipo del documento:
Article
País de afiliación:
Estados Unidos