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Synthesis and evaluation of 4,6-disubstituted pyrimidines as CNS penetrant pan-muscarinic antagonists with a novel chemotype.
- Source :
-
Bioorganic & Medicinal Chemistry Letters . Jun2017, Vol. 27 Issue 11, p2479-2483. 5p. - Publication Year :
- 2017
-
Abstract
- This letter describes the synthesis and structure activity relationship (SAR) studies of structurally novel M 4 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 M 4 (IC 50 s < 300 nM), with no substantial species differences noted. Moreover, CNS penetration proved attractive for this series (brain:plasma K p,uu = 0.87), while other DMPK attributes were addressed in the course of the optimization effort, providing low in vivo clearance in rat (CL p = 5.37 mL/min/kg). Surprisingly, this series displayed pan -muscarinic antagonist activity across M 1–5 , 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. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 0960894X
- Volume :
- 27
- Issue :
- 11
- Database :
- Academic Search Index
- Journal :
- Bioorganic & Medicinal Chemistry Letters
- Publication Type :
- Academic Journal
- Accession number :
- 122911305
- Full Text :
- https://doi.org/10.1016/j.bmcl.2017.04.009