@article{9d78900a0b18430aa53008232c00d7a6,
title = "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",
abstract = "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.",
keywords = "M, Muscarinic acetylcholine receptor, Positive allosteric modulator (PAM), Schizophrenia, Structure-Activity Relationship (SAR)",
author = "Wood, {Michael R.} and Noetzel, {Meredith J.} and Engers, {Julie L.} and Bollinger, {Katrina A.} and Melancon, {Bruce J.} and Tarr, {James C.} and Changho Han and Mary West and Gregro, {Alison R.} and Atin Lamsal and Sichen Chang and Sonia Ajmera and Emery Smith and Peter Chase and Hodder, {Peter S.} and Michael Bubser and Jones, {Carrie K.} and Hopkins, {Corey R.} and Emmitte, {Kyle A.} and Niswender, {Colleen M.} and Wood, {Michael W.} and Duggan, {Mark E.} and Conn, {P. Jeffrey} and Bridges, {Thomas M.} and Lindsley, {Craig W.}",
note = "Funding Information: We thank the NIH for funding via the NIH Roadmap Initiative 1X01 MH077607 (C.M.N.), the Molecular Libraries Probe Center Network ( U54MH084512 to P.S.H. and U54MH084659 to C.W.L.) We also thank William K. Warren, Jr. and the William K. Warren Foundation who funded the William K. Warren, Jr. Chair in Medicine (to C.W.L.). Publisher Copyright: {\textcopyright} 2016 Elsevier Ltd. All rights reserved.",
year = "2016",
month = jul,
day = "1",
doi = "10.1016/j.bmcl.2016.05.010",
language = "English",
volume = "26",
pages = "3029--3033",
journal = "Bioorganic and Medicinal Chemistry Letters",
issn = "0960-894X",
publisher = "Elsevier Ltd",
number = "13",
}