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Discovery of structurally distinct tricyclic M positive allosteric modulator (PAM) chemotypes


AUTHORS

Temple KJKayla J , Long MFMadeline F , Engers JLJulie L , Watson KJKatherine J , Chang SSichen , Luscombe VBVincent B , Rodriguez ALAlice L , Niswender CMColleen M , Bridges TMThomas M , Conn PJP Jeffrey , Engers DWDarren W , Lindsley CWCraig W . Bioorganic & medicinal chemistry letters. 2019 11 11; 30(4). 126811

ABSTRACT

This Letter details our efforts to develop new M 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 M.



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