Design and Synthesis of Clinical Candidate PF-06852231 (CVL-231): A Brain Penetrant, Selective, Positive Allosteric Modulator of the M 4 Muscarinic Acetylcholine Receptor.

Autor:	Butler CR; Medicine Design, Medicinal Chemistry, Pfizer Inc., Cambridge, Massachusetts 02139, United States., Popiolek M; Internal Medicine, Pfizer Inc., Cambridge, Massachusetts 02139, United States., McAllister LA; Medicine Design, Medicinal Chemistry, Pfizer Inc., Cambridge, Massachusetts 02139, United States., LaChapelle EA; Medicine Design, Medicinal Chemistry, Pfizer Inc., Groton, Connecticut 06340, United States., Kramer M; Medicine Design, Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc., Groton, Connecticut 06340, United States., Beck EM; Medicine Design, Medicinal Chemistry, Pfizer Inc., Cambridge, Massachusetts 02139, United States., Mente S; Medicine Design, Medicinal Chemistry, Pfizer Inc., Cambridge, Massachusetts 02139, United States., Brodney MA; Medicine Design, Medicinal Chemistry, Pfizer Inc., Cambridge, Massachusetts 02139, United States., Brown M; Medicine Design, Medicinal Chemistry, Pfizer Inc., Groton, Connecticut 06340, United States., Gilbert A; Medicine Design, Medicinal Chemistry, Pfizer Inc., Groton, Connecticut 06340, United States., Helal C; Medicine Design, Medicinal Chemistry, Pfizer Inc., Groton, Connecticut 06340, United States., Ogilvie K; Medicine Design, Medicinal Chemistry, Pfizer Inc., Groton, Connecticut 06340, United States., Starr J; Medicine Design, Medicinal Chemistry, Pfizer Inc., Groton, Connecticut 06340, United States., Uccello D; Medicine Design, Medicinal Chemistry, Pfizer Inc., Groton, Connecticut 06340, United States., Grimwood S; Internal Medicine, Pfizer Inc., Cambridge, Massachusetts 02139, United States., Edgerton J; Internal Medicine, Pfizer Inc., Cambridge, Massachusetts 02139, United States., Garst-Orozco J; Internal Medicine, Pfizer Inc., Cambridge, Massachusetts 02139, United States., Kozak R; Internal Medicine, Pfizer Inc., Cambridge, Massachusetts 02139, United States., Lotarski S; Internal Medicine, Pfizer Inc., Cambridge, Massachusetts 02139, United States., Rossi A; Internal Medicine, Pfizer Inc., Cambridge, Massachusetts 02139, United States., Smith D; Internal Medicine, Pfizer Inc., Cambridge, Massachusetts 02139, United States., O'Connor R; Discovery Sciences, Primary Pharmacology, Pfizer Inc., Groton, Connecticut 06340, United States., Lazzaro J; Discovery Sciences, Primary Pharmacology, Pfizer Inc., Groton, Connecticut 06340, United States., Steppan C; Discovery Sciences, Primary Pharmacology, Pfizer Inc., Groton, Connecticut 06340, United States., Steyn SJ; Medicine Design, Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc., Groton, Connecticut 06340, United States.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2024 Jul 11; Vol. 67 (13), pp. 10831-10847. Date of Electronic Publication: 2024 Jun 18.
DOI:	10.1021/acs.jmedchem.4c00293
Abstrakt:	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.
Databáze:	MEDLINE
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