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SAR inspired by aldehyde oxidase (AO) metabolism: Discovery of novel, CNS penetrant tricyclic M4 PAMs
- Source :
- Bioorganic & Medicinal Chemistry Letters. 29:2224-2228
- Publication Year :
- 2019
- Publisher :
- Elsevier BV, 2019.
-
Abstract
- This letter describes progress towards an M4 PAM preclinical candidate inspired by an unexpected aldehyde oxidase (AO) metabolite of a novel, CNS penetrant thieno[2,3-c]pyridine core to an equipotent, non-CNS penetrant thieno[2,3-c]pyrdin-7(6H)-one core. Medicinal chemistry design efforts yielded two novel tricyclic cores that enhanced M4 PAM potency, regained CNS penetration, displayed favorable DMPK properties and afforded robust in vivo efficacy in reversing amphetamine-induced hyperlocomotion in rats.
- Subjects :
- chemistry.chemical_classification
010405 organic chemistry
Stereochemistry
Metabolite
Organic Chemistry
Clinical Biochemistry
Pharmaceutical Science
Metabolism
01 natural sciences
Biochemistry
0104 chemical sciences
Cns penetration
010404 medicinal & biomolecular chemistry
chemistry.chemical_compound
chemistry
In vivo
Drug Discovery
Molecular Medicine
Penetrant (biochemical)
Molecular Biology
Aldehyde oxidase
Tricyclic
Subjects
Details
- ISSN :
- 0960894X
- Volume :
- 29
- Database :
- OpenAIRE
- Journal :
- Bioorganic & Medicinal Chemistry Letters
- Accession number :
- edsair.doi...........c29ef3365adcf94a1df6de7318989723