VU6009543 (CAS: 2148924-04-1 )
Background Information of VU6009543
VU6009543 is an muscarinic acetylcholine receptor subtype 4 (M4) positive allosteric modulator (PAM) with an EC50 of 1130 nM for rM4. M4 PAMs have garnered a great deal of attention as a new therapeutic approach for the treatment of schizophrenia (both the positive and cognitive symptom clusters), Huntington’s disease and Parkinson’s disease.
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Mechanism and Indications
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Structure Information of VU6009543
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Chemical and Physical Properties
.Long MF, et al. Discovery of a novel 2,4-dimethylquinoline-6-carboxamide M4 positive allosteric modulator (PAM) chemotype via scaffold hopping. Bioorg Med Chem Lett. 2017 Nov 15;27(22):4999-5001.
This Letter details our efforts to replace the 3-amino moiety, an essential pharmacophore for M4 PAM activity in most M4 PAMs to date, within the thieno[2,3-b]pyridine core, as the β-amino carboxamide motif has been shown to engender poor solubility, varying degrees of P-gp efflux and represents a structural alert. A scaffold hopping exercise identified a novel 2,4-dimethylquinoline carboxamide core that provided M4 PAM activity and good CNS penetration without an amino moiety. In addition, MacMillan photoredox catalysis chemistry was essential for construction of the 2,4-dimethylquinoline core.