Design and Synthesis of Clinical Candidate PF-06852231 (CVL-231): A Brain Penetrant, Selective, Positive Allosteric Modulator of the M<sub>4</sub> Muscarinic Acetylcholine Receptor
Christopher R. Butler, Michael Popiolek, Laura A. McAllister, Erik LaChapelle, Melissa Kramer, Elizabeth M. Beck, Scot Mente, Michael A. Brodney, Matthew F. Brown, A. Gilbert, Chris Helal, Kevin Ogilvie, Jeremy T. Starr, Daniel P. Uccello, Sarah Grimwood, Jeremy R. Edgerton, Jonathan Garst-Orozco, Rouba Kozak, Susan M. Lotarski, Amie Rossi, Deborah L. Smith, Rebecca E. O’Connor, John T. Lazzaro, Claire M. Steppan, Stefanus J. Steyn
Abstract
Selective activation of the M 4 muscarinic acetylcholine receptor subtype offers a novel strategy for the treatment of psychosis in multiple neurological disorders. Although the development of traditional muscarinic activators has been stymied due to pan-receptor activation, muscarinic receptor subtype selectivity can be achieved through the utilization of a subtype of a unique allosteric site. A major challenge in capitalizing on this allosteric site to date has been achieving a balance of suitable potency and brain penetration. Herein, we describe the design of a brain penetrant series of M 4 selective positive allosteric modulators (PAMs), ultimately culminating in the identification of 21 ( PF-06852231, now CVL-231/emraclidine), which is under active clinical development as a novel mechanism and approach for the treatment of schizophrenia.