Discovery of (R)-(2-fluoro-4-((-4-methoxyphenyl)ethynyl)phenyl) (3-hydroxypiperidin-1-yl)methanone (ML337), an mGlu3 selective and CNS penetrant negative allosteric modulator (NAM)

Cody J. Wenthur; Ryan Morrison; Andrew S. Felts; Katrina A. Smith; Julie L. Engers; Frank W. Byers; J. Scott Daniels; Kyle A. Emmitte; P. Jeffrey Conn; Craig W. Lindsley

doi:10.1021/jm400439t

Discovery of (R)-(2-fluoro-4-((-4-methoxyphenyl)ethynyl)phenyl) (3-hydroxypiperidin-1-yl)methanone (ML337), an mGlu₃ selective and CNS penetrant negative allosteric modulator (NAM)

Cody J. Wenthur, Ryan Morrison, Andrew S. Felts, Katrina A. Smith, Julie L. Engers, Frank W. Byers, J. Scott Daniels, Kyle A. Emmitte, P. Jeffrey Conn, Craig W. Lindsley

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

45 Scopus citations

Abstract

A multidimensional, iterative parallel synthesis effort identified a series of highly selective mGlu₃ NAMs with submicromolar potency and good CNS penetration. Of these, ML337 resulted (mGlu₃ IC₅₀ = 593 nM, mGlu₂ IC₅₀ >30 μM) with B:P ratios of 0.92 (mouse) to 0.3 (rat). DMPK profiling and shallow SAR led to the incorporation of deuterium atoms to address a metabolic soft spot, which subsequently lowered both in vitro and in vivo clearance by >50%.

Original language	English
Pages (from-to)	5208-5212
Number of pages	5
Journal	Journal of Medicinal Chemistry
Volume	56
Issue number	12
DOIs	https://doi.org/10.1021/jm400439t
State	Published - 27 Jun 2013

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Wenthur, C. J., Morrison, R., Felts, A. S., Smith, K. A., Engers, J. L., Byers, F. W., Daniels, J. S., Emmitte, K. A., Conn, P. J., & Lindsley, C. W. (2013). Discovery of (R)-(2-fluoro-4-((-4-methoxyphenyl)ethynyl)phenyl) (3-hydroxypiperidin-1-yl)methanone (ML337), an mGlu₃ selective and CNS penetrant negative allosteric modulator (NAM). Journal of Medicinal Chemistry, 56(12), 5208-5212. https://doi.org/10.1021/jm400439t

@article{e0df4f90fe3a4403a5b6ba95c895ecd1,

title = "Discovery of (R)-(2-fluoro-4-((-4-methoxyphenyl)ethynyl)phenyl) (3-hydroxypiperidin-1-yl)methanone (ML337), an mGlu3 selective and CNS penetrant negative allosteric modulator (NAM)",

abstract = "A multidimensional, iterative parallel synthesis effort identified a series of highly selective mGlu3 NAMs with submicromolar potency and good CNS penetration. Of these, ML337 resulted (mGlu3 IC50 = 593 nM, mGlu2 IC50 >30 μM) with B:P ratios of 0.92 (mouse) to 0.3 (rat). DMPK profiling and shallow SAR led to the incorporation of deuterium atoms to address a metabolic soft spot, which subsequently lowered both in vitro and in vivo clearance by >50%.",

author = "Wenthur, {Cody J.} and Ryan Morrison and Felts, {Andrew S.} and Smith, {Katrina A.} and Engers, {Julie L.} and Byers, {Frank W.} and Daniels, {J. Scott} and Emmitte, {Kyle A.} and Conn, {P. Jeffrey} and Lindsley, {Craig W.}",

year = "2013",

month = jun,

day = "27",

doi = "10.1021/jm400439t",

language = "English",

volume = "56",

pages = "5208--5212",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

number = "12",

}

Wenthur, CJ, Morrison, R, Felts, AS, Smith, KA, Engers, JL, Byers, FW, Daniels, JS, Emmitte, KA, Conn, PJ & Lindsley, CW 2013, 'Discovery of (R)-(2-fluoro-4-((-4-methoxyphenyl)ethynyl)phenyl) (3-hydroxypiperidin-1-yl)methanone (ML337), an mGlu₃ selective and CNS penetrant negative allosteric modulator (NAM)', Journal of Medicinal Chemistry, vol. 56, no. 12, pp. 5208-5212. https://doi.org/10.1021/jm400439t

Discovery of (R)-(2-fluoro-4-((-4-methoxyphenyl)ethynyl)phenyl) (3-hydroxypiperidin-1-yl)methanone (ML337), an mGlu₃ selective and CNS penetrant negative allosteric modulator (NAM). / Wenthur, Cody J.; Morrison, Ryan; Felts, Andrew S. et al.

In: Journal of Medicinal Chemistry, Vol. 56, No. 12, 27.06.2013, p. 5208-5212.

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

TY - JOUR

T1 - Discovery of (R)-(2-fluoro-4-((-4-methoxyphenyl)ethynyl)phenyl) (3-hydroxypiperidin-1-yl)methanone (ML337), an mGlu3 selective and CNS penetrant negative allosteric modulator (NAM)

AU - Wenthur, Cody J.

AU - Morrison, Ryan

AU - Felts, Andrew S.

AU - Smith, Katrina A.

AU - Engers, Julie L.

AU - Byers, Frank W.

AU - Daniels, J. Scott

AU - Emmitte, Kyle A.

AU - Conn, P. Jeffrey

AU - Lindsley, Craig W.

PY - 2013/6/27

Y1 - 2013/6/27

N2 - A multidimensional, iterative parallel synthesis effort identified a series of highly selective mGlu3 NAMs with submicromolar potency and good CNS penetration. Of these, ML337 resulted (mGlu3 IC50 = 593 nM, mGlu2 IC50 >30 μM) with B:P ratios of 0.92 (mouse) to 0.3 (rat). DMPK profiling and shallow SAR led to the incorporation of deuterium atoms to address a metabolic soft spot, which subsequently lowered both in vitro and in vivo clearance by >50%.

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ER -

Discovery of (R)-(2-fluoro-4-((-4-methoxyphenyl)ethynyl)phenyl) (3-hydroxypiperidin-1-yl)methanone (ML337), an mGlu₃ selective and CNS penetrant negative allosteric modulator (NAM)

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