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Discovery and optimization of a novel, selective and brain penetrant M1 positive allosteric modulator (PAM): the development of ML169, an MLPCN probe.

AUTHORS

Reid PRPaul R , Bridges TM Thomas M , Sheffler DJ Douglas J , Cho HP Hyekyung P , Lewis LM L Michelle , Days E Emily , Daniels JS J Scott , Jones CK Carrie K , Niswender CM Colleen M , Weaver CD C David , Conn PJ P Jeffrey , Lindsley CW Craig W , Wood MR Michael R . Bioorganic & medicinal chemistry letters. 2011 5 1; 21(9). 2697-701

ABSTRACT

This Letter describes a chemical lead optimization campaign directed at VU0108370, a weak M(1) PAM hit with a novel chemical scaffold from a functional HTS screen within the MLPCN. An iterative parallel synthesis approach rapidly established SAR for this series and afforded VU0405652 (ML169), a potent, selective and brain penetrant M(1) PAM with an in vitro profile comparable to the prototypical M(1) PAM, BQCA, but with an improved brain to plasma ratio.

This Letter describes a chemical lead optimization campaign directed at VU0108370, a weak M(1) PAM hit with a novel chemical scaffold from a functional HTS screen within the MLPCN. An iterative parallel synthesis approach rapidly established SAR for this series and afforded VU0405652 (ML169), a potent, selective and brain penetrant M(1) PAM with an in vitro profile comparable to the prototypical M(1) PAM, BQCA, but with an improved brain to plasma ratio.