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Discovery of structurally distinct tricyclic M4 positive allosteric modulator (PAM) chemotypes
- Source :
- Bioorganic & Medicinal Chemistry Letters. 30:126811
- Publication Year :
- 2020
- Publisher :
- Elsevier BV, 2020.
-
Abstract
- This Letter details our efforts to develop new M4 PAM scaffolds with improved pharmacological properties. This endeavor involved replacing the 3,4-dimethylpyridazine core with two novel cores: a 2,3-dimethyl-2H-indazole-5-carboxamide core or a 1-methyl-1H-benzo[d][1,2,3]triazole-6-carboxamide core. Due to shallow SAR, these cores were further evolved into two unique tricyclic cores: an 8,9-dimethyl-8H-pyrazolo[3,4-h]quinazoline core and an 1-methyl-1H-[1,2,3]triazolo[4,5-h]quinazoline core. Both tricyclic cores displayed low nanomolar potency against both human and rat M4.
- Subjects :
- chemistry.chemical_classification
Allosteric modulator
010405 organic chemistry
Stereochemistry
Chemistry
Organic Chemistry
Clinical Biochemistry
Pharmaceutical Science
01 natural sciences
Biochemistry
0104 chemical sciences
010404 medicinal & biomolecular chemistry
chemistry.chemical_compound
Drug Discovery
Quinazoline
Molecular Medicine
Molecular Biology
Tricyclic
Subjects
Details
- ISSN :
- 0960894X
- Volume :
- 30
- Database :
- OpenAIRE
- Journal :
- Bioorganic & Medicinal Chemistry Letters
- Accession number :
- edsair.doi...........b357d1915985128a63e2a37346709cc5