Discovery and optimization of a novel series of highly CNS penetrant M4 PAMs based on a 5,6-dimethyl-4-(piperidin-1-yl)thieno[2,3-d]pyrimidine core

• Published in: Bioorganic & medicinal chemistry letters Vol. 26; no. 13; pp. 3029 - 3033
• Main Authors: Wood, Michael R., Noetzel, Meredith J., Engers, Julie L., Bollinger, Katrina A., Melancon, Bruce J., Tarr, James C., Han, Changho, West, Mary, Gregro, Alison R., Lamsal, Atin, Chang, Sichen, Ajmera, Sonia, Smith, Emery, Chase, Peter, Hodder, Peter S., Bubser, Michael, Jones, Carrie K., Hopkins, Corey R., Emmitte, Kyle A., Niswender, Colleen M., Wood, Michael W., Duggan, Mark E., Conn, P. Jeffrey, Bridges, Thomas M., Lindsley, Craig W.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.07.2016
• Subjects: Allosteric Regulation; Animals; Brain - drug effects; Brain - metabolism; Humans; Microsomes, Liver - metabolism; Muscarinic acetylcholine receptor; Piperidines - chemical synthesis; Piperidines - metabolism; Piperidines - pharmacology; Positive allosteric modulator (PAM); Pyrimidines - chemical synthesis; Pyrimidines - metabolism; Pyrimidines - pharmacology; Quinazolines - chemical synthesis; Quinazolines - metabolism; Quinazolines - pharmacology; Rats; Receptor, Muscarinic M4 - agonists; Receptor, Muscarinic M4 - antagonists & inhibitors; Receptor, Muscarinic M4 - metabolism; Schizophrenia; Structure-Activity Relationship; Structure–Activity Relationship (SAR); Thiophenes - chemical synthesis; Thiophenes - metabolism; Thiophenes - pharmacology; Schizophrenia; Positive allosteric modulator (PAM); M4; Structure–Activity Relationship (SAR); Muscarinic acetylcholine receptor; M
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2016.05.010

[Display omitted] This Letter describes the chemical optimization of a novel series of M4 positive allosteric modulators (PAMs) based on a 5,6-dimethyl-4-(piperidin-1-yl)thieno[2,3-d]pyrimidine core, identified from an MLPCN functional high-throughput screen. The HTS hit was potent and selective, but not CNS penetrant. Potency was maintained, while CNS penetration was improved (rat brain:plasma Kp=0.74), within the original core after several rounds of optimization; however, the thieno[2,3-d]pyrimidine core was subject to extensive oxidative metabolism. Ultimately, we identified a 6-fluoroquinazoline core replacement that afforded good M4 PAM potency, muscarinic receptor subtype selectivity and CNS penetration (rat brain:plasma Kp>10). Moreover, this campaign provided fundamentally distinct M4 PAM chemotypes, greatly expanding the available structural diversity for this exciting CNS target.