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

Michael R. Wood; Meredith J. Noetzel; Julie L. Engers; Katrina A. Bollinger; Bruce J. Melancon; James C. Tarr; Changho Han; Mary West; Alison R. Gregro; Atin Lamsal; Sichen Chang; Sonia Ajmera; Emery Smith; Peter Chase; Peter S. Hodder; Michael Bubser; Carrie K. Jones; Corey R. Hopkins; Kyle A. Emmitte; Colleen M. Niswender; Michael W. Wood; Mark E. Duggan; P. Jeffrey Conn; Thomas M. Bridges; Craig W. Lindsley

doi:10.1016/j.bmcl.2016.05.010

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

Michael R. Wood, Meredith J. Noetzel, Julie L. Engers, Katrina A. Bollinger, Bruce J. Melancon, James C. Tarr, Changho Han, Mary West, Alison R. Gregro, Atin Lamsal, Sichen Chang, Sonia Ajmera, Emery Smith, Peter Chase, Peter S. Hodder, Michael Bubser, Carrie K. Jones, Corey R. Hopkins, Kyle A. Emmitte, Colleen M. NiswenderMichael W. Wood, Mark E. Duggan, P. Jeffrey Conn, Thomas M. Bridges, Craig W. Lindsley

Research output: Contribution to journal › Article › peer-review

20 Scopus citations

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 K_p = 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 K_p > 10). Moreover, this campaign provided fundamentally distinct M₄ PAM chemotypes, greatly expanding the available structural diversity for this exciting CNS target.

Original language	English
Pages (from-to)	3029-3033
Number of pages	5
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	26
Issue number	13
DOIs	https://doi.org/10.1016/j.bmcl.2016.05.010
State	Published - 1 Jul 2016

Keywords

M
Muscarinic acetylcholine receptor
Positive allosteric modulator (PAM)
Schizophrenia
Structure-Activity Relationship (SAR)

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10.1016/j.bmcl.2016.05.010

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Wood, M. R., Noetzel, M. J., Engers, J. L., Bollinger, K. A., Melancon, B. J., Tarr, J. C., Han, C., West, M., Gregro, A. R., Lamsal, A., Chang, S., Ajmera, S., Smith, E., Chase, P., Hodder, P. S., Bubser, M., Jones, C. K., Hopkins, C. R., Emmitte, K. A., ... Lindsley, C. W. (2016). 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. Bioorganic and Medicinal Chemistry Letters, 26(13), 3029-3033. https://doi.org/10.1016/j.bmcl.2016.05.010

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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",

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Wood, MR, Noetzel, MJ, Engers, JL, Bollinger, KA, Melancon, BJ, Tarr, JC, Han, C, West, M, Gregro, AR, Lamsal, A, Chang, S, Ajmera, S, Smith, E, Chase, P, Hodder, PS, Bubser, M, Jones, CK, Hopkins, CR, Emmitte, KA, Niswender, CM, Wood, MW, Duggan, ME, Conn, PJ, Bridges, TM & Lindsley, CW 2016, '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', Bioorganic and Medicinal Chemistry Letters, vol. 26, no. 13, pp. 3029-3033. https://doi.org/10.1016/j.bmcl.2016.05.010

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. / Wood, Michael R.; Noetzel, Meredith J.; Engers, Julie L. et al.
In: Bioorganic and Medicinal Chemistry Letters, Vol. 26, No. 13, 01.07.2016, p. 3029-3033.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - 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

AU - Wood, Michael R.

AU - Noetzel, Meredith J.

AU - Engers, Julie L.

AU - Bollinger, Katrina A.

AU - Melancon, Bruce J.

AU - Tarr, James C.

AU - Han, Changho

AU - West, Mary

AU - Gregro, Alison R.

AU - Lamsal, Atin

AU - Chang, Sichen

AU - Ajmera, Sonia

AU - Smith, Emery

AU - Chase, Peter

AU - Hodder, Peter S.

AU - Bubser, Michael

AU - Jones, Carrie K.

AU - Hopkins, Corey R.

AU - Emmitte, Kyle A.

AU - Niswender, Colleen M.

AU - Wood, Michael W.

AU - Duggan, Mark E.

AU - Conn, P. Jeffrey

AU - Bridges, Thomas M.

AU - Lindsley, Craig W.

N1 - 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: © 2016 Elsevier Ltd. All rights reserved.

PY - 2016/7/1

Y1 - 2016/7/1

N2 - 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.

AB - 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.

KW - M

KW - Muscarinic acetylcholine receptor

KW - Positive allosteric modulator (PAM)

KW - Schizophrenia

KW - Structure-Activity Relationship (SAR)

UR - http://www.scopus.com/inward/record.url?scp=84966545988&partnerID=8YFLogxK

U2 - 10.1016/j.bmcl.2016.05.010

DO - 10.1016/j.bmcl.2016.05.010

M3 - Article

C2 - 27185330

AN - SCOPUS:84966545988

SN - 0960-894X

VL - 26

SP - 3029

EP - 3033

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

IS - 13

ER -

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

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Keywords

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