N-Alkylpyrido[1′,2′:1,5]pyrazolo-[4,3-d]pyrimidin-4-amines: A new series of negative allosteric modulators of mGlu1/5 with CNS exposure in rodents

Andrew S. Felts; Alice L. Rodriguez; Ryan D. Morrison; Daryl F. Venable; Anna L. Blobaum; Frank W. Byers; J. Scott Daniels; Colleen M. Niswender; Carrie K. Jones; P. Jeffrey Conn; Craig W. Lindsley; Kyle A. Emmitte

doi:10.1016/j.bmcl.2016.03.026

N-Alkylpyrido[1′,2′:1,5]pyrazolo-[4,3-d]pyrimidin-4-amines: A new series of negative allosteric modulators of mGlu_1/5 with CNS exposure in rodents

Andrew S. Felts, Alice L. Rodriguez, Ryan D. Morrison, Daryl F. Venable, Anna L. Blobaum, Frank W. Byers, J. Scott Daniels, Colleen M. Niswender, Carrie K. Jones, P. Jeffrey Conn, Craig W. Lindsley, Kyle A. Emmitte

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

9 Scopus citations

Abstract

Selective negative allosteric modulators (NAMs) of each of the group I metabotropic glutamate receptors (mGlu₁ and mGlu₅) have been well characterized in the literature and offer potential as therapeutics in several disorders of the central nervous system (CNS). Still, compounds that are potent mGlu_1/5 NAMs with selectivity versus the other six members of the mGlu family as well as the balance of properties required for use in vivo are lacking. A medicinal chemistry effort centered on the identification of a lead series with the potential of delivering such compounds is described in this Letter. Specifically, a new class of pyrido[1′,2′:1,5]pyrazolo[4,3-d]pyrimidin-4-amines was designed as a novel isosteric replacement for 4-aminoquinazolines, and compounds from within this chemotype exhibited dual NAM activity at both group I mGlus. One compound, VU0467558 (29), demonstrated near equipotent activity at both receptors, selectivity versus other mGlus, a favorable ancillary pharmacology profile, and CNS exposure in rodents.

Original language	English
Pages (from-to)	1894-1900
Number of pages	7
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	26
Issue number	8
DOIs	https://doi.org/10.1016/j.bmcl.2016.03.026
State	Published - 15 Apr 2016

Keywords

Central nervous system (CNS)
G-protein coupled receptor (GPCR)
Metabotropic glutamate receptor subtype 1 (mGlu)
Metabotropic glutamate receptor subtype 5 (mGlu)
Negative allosteric modulator (NAM)

Access to Document

10.1016/j.bmcl.2016.03.026

Cite this

Felts, A. S., Rodriguez, A. L., Morrison, R. D., Venable, D. F., Blobaum, A. L., Byers, F. W., Daniels, J. S., Niswender, C. M., Jones, C. K., Conn, P. J., Lindsley, C. W., & Emmitte, K. A. (2016). N-Alkylpyrido[1′,2′:1,5]pyrazolo-[4,3-d]pyrimidin-4-amines: A new series of negative allosteric modulators of mGlu_1/5 with CNS exposure in rodents. Bioorganic and Medicinal Chemistry Letters, 26(8), 1894-1900. https://doi.org/10.1016/j.bmcl.2016.03.026

@article{ae6ea6a02ed54b9b996f3b40fc1b50ee,

title = "N-Alkylpyrido[1′,2′:1,5]pyrazolo-[4,3-d]pyrimidin-4-amines: A new series of negative allosteric modulators of mGlu1/5 with CNS exposure in rodents",

abstract = "Selective negative allosteric modulators (NAMs) of each of the group I metabotropic glutamate receptors (mGlu1 and mGlu5) have been well characterized in the literature and offer potential as therapeutics in several disorders of the central nervous system (CNS). Still, compounds that are potent mGlu1/5 NAMs with selectivity versus the other six members of the mGlu family as well as the balance of properties required for use in vivo are lacking. A medicinal chemistry effort centered on the identification of a lead series with the potential of delivering such compounds is described in this Letter. Specifically, a new class of pyrido[1′,2′:1,5]pyrazolo[4,3-d]pyrimidin-4-amines was designed as a novel isosteric replacement for 4-aminoquinazolines, and compounds from within this chemotype exhibited dual NAM activity at both group I mGlus. One compound, VU0467558 (29), demonstrated near equipotent activity at both receptors, selectivity versus other mGlus, a favorable ancillary pharmacology profile, and CNS exposure in rodents.",

keywords = "Central nervous system (CNS), G-protein coupled receptor (GPCR), Metabotropic glutamate receptor subtype 1 (mGlu), Metabotropic glutamate receptor subtype 5 (mGlu), Negative allosteric modulator (NAM)",

author = "Felts, {Andrew S.} and Rodriguez, {Alice L.} and Morrison, {Ryan D.} and Venable, {Daryl F.} and Blobaum, {Anna L.} and Byers, {Frank W.} and Daniels, {J. Scott} and Niswender, {Colleen M.} and Jones, {Carrie K.} and Conn, {P. Jeffrey} and Lindsley, {Craig W.} and Emmitte, {Kyle A.}",

year = "2016",

month = apr,

day = "15",

doi = "10.1016/j.bmcl.2016.03.026",

language = "English",

volume = "26",

pages = "1894--1900",

journal = "Bioorganic and Medicinal Chemistry Letters",

issn = "0960-894X",

publisher = "Elsevier Ltd",

number = "8",

}

Felts, AS, Rodriguez, AL, Morrison, RD, Venable, DF, Blobaum, AL, Byers, FW, Daniels, JS, Niswender, CM, Jones, CK, Conn, PJ, Lindsley, CW & Emmitte, KA 2016, 'N-Alkylpyrido[1′,2′:1,5]pyrazolo-[4,3-d]pyrimidin-4-amines: A new series of negative allosteric modulators of mGlu_1/5 with CNS exposure in rodents', Bioorganic and Medicinal Chemistry Letters, vol. 26, no. 8, pp. 1894-1900. https://doi.org/10.1016/j.bmcl.2016.03.026

N-Alkylpyrido[1′,2′:1,5]pyrazolo-[4,3-d]pyrimidin-4-amines: A new series of negative allosteric modulators of mGlu_1/5 with CNS exposure in rodents. / Felts, Andrew S.; Rodriguez, Alice L.; Morrison, Ryan D. et al.
In: Bioorganic and Medicinal Chemistry Letters, Vol. 26, No. 8, 15.04.2016, p. 1894-1900.

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

TY - JOUR

T1 - N-Alkylpyrido[1′,2′:1,5]pyrazolo-[4,3-d]pyrimidin-4-amines

T2 - A new series of negative allosteric modulators of mGlu1/5 with CNS exposure in rodents

AU - Felts, Andrew S.

AU - Rodriguez, Alice L.

AU - Morrison, Ryan D.

AU - Venable, Daryl F.

AU - Blobaum, Anna L.

AU - Byers, Frank W.

AU - Daniels, J. Scott

AU - Niswender, Colleen M.

AU - Jones, Carrie K.

AU - Conn, P. Jeffrey

AU - Lindsley, Craig W.

AU - Emmitte, Kyle A.

PY - 2016/4/15

Y1 - 2016/4/15

N2 - Selective negative allosteric modulators (NAMs) of each of the group I metabotropic glutamate receptors (mGlu1 and mGlu5) have been well characterized in the literature and offer potential as therapeutics in several disorders of the central nervous system (CNS). Still, compounds that are potent mGlu1/5 NAMs with selectivity versus the other six members of the mGlu family as well as the balance of properties required for use in vivo are lacking. A medicinal chemistry effort centered on the identification of a lead series with the potential of delivering such compounds is described in this Letter. Specifically, a new class of pyrido[1′,2′:1,5]pyrazolo[4,3-d]pyrimidin-4-amines was designed as a novel isosteric replacement for 4-aminoquinazolines, and compounds from within this chemotype exhibited dual NAM activity at both group I mGlus. One compound, VU0467558 (29), demonstrated near equipotent activity at both receptors, selectivity versus other mGlus, a favorable ancillary pharmacology profile, and CNS exposure in rodents.

AB - Selective negative allosteric modulators (NAMs) of each of the group I metabotropic glutamate receptors (mGlu1 and mGlu5) have been well characterized in the literature and offer potential as therapeutics in several disorders of the central nervous system (CNS). Still, compounds that are potent mGlu1/5 NAMs with selectivity versus the other six members of the mGlu family as well as the balance of properties required for use in vivo are lacking. A medicinal chemistry effort centered on the identification of a lead series with the potential of delivering such compounds is described in this Letter. Specifically, a new class of pyrido[1′,2′:1,5]pyrazolo[4,3-d]pyrimidin-4-amines was designed as a novel isosteric replacement for 4-aminoquinazolines, and compounds from within this chemotype exhibited dual NAM activity at both group I mGlus. One compound, VU0467558 (29), demonstrated near equipotent activity at both receptors, selectivity versus other mGlus, a favorable ancillary pharmacology profile, and CNS exposure in rodents.

KW - Central nervous system (CNS)

KW - G-protein coupled receptor (GPCR)

KW - Metabotropic glutamate receptor subtype 1 (mGlu)

KW - Metabotropic glutamate receptor subtype 5 (mGlu)

KW - Negative allosteric modulator (NAM)

UR - http://www.scopus.com/inward/record.url?scp=84960517058&partnerID=8YFLogxK

U2 - 10.1016/j.bmcl.2016.03.026

DO - 10.1016/j.bmcl.2016.03.026

M3 - Article

C2 - 26988308

AN - SCOPUS:84960517058

SN - 0960-894X

VL - 26

SP - 1894

EP - 1900

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

IS - 8

ER -

N-Alkylpyrido[1′,2′:1,5]pyrazolo-[4,3-d]pyrimidin-4-amines: A new series of negative allosteric modulators of mGlu_1/5 with CNS exposure in rodents

Abstract

Keywords

Access to Document

Other files and links

Fingerprint

Cite this