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Discovery of VU6008677: A Structurally Distinct Tricyclic M4 Positive Allosteric Modulator with Improved CYP450 Profile.


ABSTRACT: This Letter details our efforts to develop novel tricyclic muscarinic acetylcholine receptor subtype 4 (M4) positive allosteric modulator (PAM) scaffolds with improved pharmacological properties. This endeavor involved a "tie-back" strategy to replace the 3-amino-5-chloro-4,6-dimethylthieno[2,3-b]pyridine-2-carboxamide core, which led to the discovery of two novel tricyclic cores: an 8-chloro-9-methylpyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-amine core and 8-chloro-7,9-dimethylpyrido[3',2':4,5]furo[3,2-d]pyrimidin-4-amine core. Both tricyclic cores displayed low nanomolar potency against human M4 and greatly reduced cytochrome P450 inhibition when compared with parent compound ML253.

SUBMITTER: Capstick RA 

PROVIDER: S-EPMC11318023 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature

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Discovery of VU6008677: A Structurally Distinct Tricyclic M<sub>4</sub> Positive Allosteric Modulator with Improved CYP450 Profile.

Capstick Rory A RA   Bollinger Sean R SR   Engers Julie L JL   Long Madeline F MF   Chang Sichen S   Luscombe Vincent B VB   Rodriguez Alice L AL   Niswender Colleen M CM   Bridges Thomas M TM   Boutaud Olivier O   Conn P Jeffrey PJ   Engers Darren W DW   Lindsley Craig W CW   Temple Kayla J KJ  

ACS medicinal chemistry letters 20240703 8


This Letter details our efforts to develop novel tricyclic muscarinic acetylcholine receptor subtype 4 (M<sub>4</sub>) positive allosteric modulator (PAM) scaffolds with improved pharmacological properties. This endeavor involved a "tie-back" strategy to replace the 3-amino-5-chloro-4,6-dimethylthieno[2,3-<i>b</i>]pyridine-2-carboxamide core, which led to the discovery of two novel tricyclic cores: an 8-chloro-9-methylpyrido[3',2':4,5]thieno[3,2-<i>d</i>]pyrimidin-4-amine core and 8-chloro-7,9-d  ...[more]

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