molecules of the month

The Takeda brain-penetrant M1R positive allosteric modulator (PAM), TAK-071, was optimized for lower cooperativity (α) with the native ligand to theoretically reduce the side effect of diarrhea from M1R activation. In animal models, higher cooperativity on M1R was associated with diarrhea, while lower cooperativity led to a wider margin. In this first-in-human study, TAK-071 appears to safe and well tolerated in humans, with notably uncommon nausea, vomiting, or diarrhea effects typical of cholinergic agents. TAK-071 demonstrates a long half-life of ~46-60 h with excellent brain penetration at a low dose, which is impressive for a molecule containing a secondary alcohol and THP ring. A Ph. II trial for Parkinson’s appears to be actively enrolling (NCT04334317) with a sentinel dose of…