Abstract
This letter describes the first account of the chemical optimization (SAR and DMPK profiling) of a new series of mGlu4 positive allosteric modulators (PAMs), leading to the identification of VU0652957 (VU2957, Valiglurax), a compound profiled as a preclinical development candidate. Here, we detail the challenges faced in allosteric modulator programs (e.g., steep SAR, as well as subtle structural changes affecting overall physiochemical/DMPK properties and CNS penetration).
| Original language | English |
|---|---|
| Pages (from-to) | 342-346 |
| Number of pages | 5 |
| Journal | Bioorganic and Medicinal Chemistry Letters |
| Volume | 29 |
| Issue number | 2 |
| DOIs | |
| State | Published - 15 Jan 2019 |
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Keywords
- Metabotropic glutamate receptor
- Parkinson's disease (PD)
- Positive allosteric modulator (PAM)
- Structure-activity relationship (SAR)
- mGlu
Cite this
}
The discovery of VU0652957 (VU2957, Valiglurax) : SAR and DMPK challenges en route to an mGlu4 PAM development candidate. / Panarese, Joseph D.; Engers, Darren W.; Wu, Yong Jin; Guernon, Jason M.; Chun, Aspen; Gregro, Alison R.; Bender, Aaron M.; Capstick, Rory A.; Wieting, Joshua M.; Bronson, Joanne J.; Macor, John E.; Westphal, Ryan; Soars, Matthew; Engers, Julie E.; Felts, Andrew S.; Rodriguez, Alice L.; Emmitte, Kyle A.; Jones, Carrie K.; Blobaum, Anna L.; Jeffrey Conn, P.; Niswender, Colleen M.; Hopkins, Corey R.; Lindsley, Craig W.
In: Bioorganic and Medicinal Chemistry Letters, Vol. 29, No. 2, 15.01.2019, p. 342-346.Research output: Contribution to journal › Article
TY - JOUR
T1 - The discovery of VU0652957 (VU2957, Valiglurax)
T2 - SAR and DMPK challenges en route to an mGlu4 PAM development candidate
AU - Panarese, Joseph D.
AU - Engers, Darren W.
AU - Wu, Yong Jin
AU - Guernon, Jason M.
AU - Chun, Aspen
AU - Gregro, Alison R.
AU - Bender, Aaron M.
AU - Capstick, Rory A.
AU - Wieting, Joshua M.
AU - Bronson, Joanne J.
AU - Macor, John E.
AU - Westphal, Ryan
AU - Soars, Matthew
AU - Engers, Julie E.
AU - Felts, Andrew S.
AU - Rodriguez, Alice L.
AU - Emmitte, Kyle A.
AU - Jones, Carrie K.
AU - Blobaum, Anna L.
AU - Jeffrey Conn, P.
AU - Niswender, Colleen M.
AU - Hopkins, Corey R.
AU - Lindsley, Craig W.
PY - 2019/1/15
Y1 - 2019/1/15
N2 - This letter describes the first account of the chemical optimization (SAR and DMPK profiling) of a new series of mGlu4 positive allosteric modulators (PAMs), leading to the identification of VU0652957 (VU2957, Valiglurax), a compound profiled as a preclinical development candidate. Here, we detail the challenges faced in allosteric modulator programs (e.g., steep SAR, as well as subtle structural changes affecting overall physiochemical/DMPK properties and CNS penetration).
AB - This letter describes the first account of the chemical optimization (SAR and DMPK profiling) of a new series of mGlu4 positive allosteric modulators (PAMs), leading to the identification of VU0652957 (VU2957, Valiglurax), a compound profiled as a preclinical development candidate. Here, we detail the challenges faced in allosteric modulator programs (e.g., steep SAR, as well as subtle structural changes affecting overall physiochemical/DMPK properties and CNS penetration).
KW - Metabotropic glutamate receptor
KW - Parkinson's disease (PD)
KW - Positive allosteric modulator (PAM)
KW - Structure-activity relationship (SAR)
KW - mGlu
UR - http://www.scopus.com/inward/record.url?scp=85057471964&partnerID=8YFLogxK
U2 - 10.1016/j.bmcl.2018.10.050
DO - 10.1016/j.bmcl.2018.10.050
M3 - Article
C2 - 30503632
AN - SCOPUS:85057471964
VL - 29
SP - 342
EP - 346
JO - Bioorganic and Medicinal Chemistry Letters
JF - Bioorganic and Medicinal Chemistry Letters
SN - 0960-894X
IS - 2
ER -