Discovery of structurally distinct tricyclic M 4 positive allosteric modulator (PAM) chemotypes - Part 2

This Letter details our efforts to develop novel tricyclic M PAM scaffolds with improved pharmacological properties. This endeavor involved a "tie-back" strategy to replace the 3-amino-4,6-dimethylthieno[2,3-b]pyridine-2-carboxamide core which lead to the discovery of two novel tricyclic c...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2021-12, Vol.53, p.128416
Hauptverfasser:	Long, Madeline F, Capstick, Rory A, Spearing, Paul K, Engers, Julie L, Gregro, Alison R, Bollinger, Sean R, Chang, Sichen, Luscombe, Vincent B, Rodriguez, Alice L, Cho, Hyekyung P, Niswender, Colleen M, Bridges, Thomas M, Conn, P Jeffrey, Lindsley, Craig W, Engers, Darren W, Temple, Kayla J
Format:	Artikel
Sprache:	eng
Schlagworte:	Dose-Response Relationship, Drug Drug Discovery Humans Molecular Structure Pyrimidines - chemical synthesis Pyrimidines - chemistry Pyrimidines - pharmacology Receptor, Muscarinic M4 - antagonists & inhibitors Receptor, Muscarinic M4 - metabolism Structure-Activity Relationship
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Zusammenfassung:	This Letter details our efforts to develop novel tricyclic M PAM scaffolds with improved pharmacological properties. This endeavor involved a "tie-back" strategy to replace the 3-amino-4,6-dimethylthieno[2,3-b]pyridine-2-carboxamide core which lead to the discovery of two novel tricyclic cores: a 7,9-dimethylpyrido[3',2':4,5]thieno[3,2-d]pyrimidine core and 2,4-dimethylthieno[2,3-b:5,4-c']dipyridine core. Both tricyclic cores displayed low nanomolar potency against the human M receptor.
ISSN:	1464-3405
DOI:	10.1016/j.bmcl.2021.128416