Design and Synthesis of Clinical Candidate PF-06852231 (CVL-231): A Brain Penetrant, Selective, Positive Allosteric Modulator of the M4 Muscarinic Acetylcholine Receptor

• Published in: Journal of medicinal chemistry Vol. 67; no. 13; pp. 10831 - 10847
• Main Authors: Butler, Christopher R., Popiolek, Michael, McAllister, Laura A., LaChapelle, Erik A., Kramer, Melissa, Beck, Elizabeth M., Mente, Scot, Brodney, Michael A., Brown, Matthew, Gilbert, Adam, Helal, Chris, Ogilvie, Kevin, Starr, Jeremy, Uccello, Daniel, Grimwood, Sarah, Edgerton, Jeremy, Garst-Orozco, Jonathan, Kozak, Rouba, Lotarski, Susan, Rossi, Amie, Smith, Deborah, O’Connor, Rebecca, Lazzaro, John, Steppan, Claire, Steyn, Stefanus J.
• Format: Journal Article
• Language: English
• Published: American Chemical Society 11.07.2024
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/acs.jmedchem.4c00293

Selective activation of the M4 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 M4 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.