Abstract
This letter describes the further chemical optimization of VU0424238 (auglurant), an mGlu 5 NAM clinical candidate that failed in non-human primate (NHP) 28 day toxicology due to accumulation of a species-specific aldehyde oxidase (AO) metabolite of the pyrimidine head group. Here, we excised the pyrimidine moiety, identified the minimum pharmacophore, and then developed a new series of saturated ether head groups that ablated any AO contribution to metabolism. Putative back-up compounds in this novel series provided increased sp 3 character, uniform CYP 450 -mediated metabolism across species, good functional potency and high CNS penetration. Key to the optimization was a combination of matrix and iterative libraries that allowed rapid surveillance of multiple domains of the allosteric ligand.
| Original language | English |
|---|---|
| Pages (from-to) | 47-50 |
| Number of pages | 4 |
| Journal | Bioorganic and Medicinal Chemistry Letters |
| Volume | 29 |
| Issue number | 1 |
| DOIs | |
| State | Published - 1 Jan 2019 |
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Keywords
- CNS
- Metabotropic glutamate receptor
- Negative allosteric modulator (NAM)
- Structure-Activity Relationship (SAR)
- mGlu
Cite this
}
Discovery of 4-alkoxy-6-methylpicolinamide negative allosteric modulators of metabotropic glutamate receptor subtype 5. / Felts, Andrew S.; Bollinger, Katrina A.; Brassard, Christopher J.; Rodriguez, Alice L.; Morrison, Ryan D.; Scott Daniels, J.; Blobaum, Anna L.; Niswender, Colleen M.; Jones, Carrie K.; Jeffrey Conn, P.; Emmitte, Kyle Allen; Lindsley, Craig W.
In: Bioorganic and Medicinal Chemistry Letters, Vol. 29, No. 1, 01.01.2019, p. 47-50.Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - Discovery of 4-alkoxy-6-methylpicolinamide negative allosteric modulators of metabotropic glutamate receptor subtype 5
AU - Felts, Andrew S.
AU - Bollinger, Katrina A.
AU - Brassard, Christopher J.
AU - Rodriguez, Alice L.
AU - Morrison, Ryan D.
AU - Scott Daniels, J.
AU - Blobaum, Anna L.
AU - Niswender, Colleen M.
AU - Jones, Carrie K.
AU - Jeffrey Conn, P.
AU - Emmitte, Kyle Allen
AU - Lindsley, Craig W.
PY - 2019/1/1
Y1 - 2019/1/1
N2 - This letter describes the further chemical optimization of VU0424238 (auglurant), an mGlu 5 NAM clinical candidate that failed in non-human primate (NHP) 28 day toxicology due to accumulation of a species-specific aldehyde oxidase (AO) metabolite of the pyrimidine head group. Here, we excised the pyrimidine moiety, identified the minimum pharmacophore, and then developed a new series of saturated ether head groups that ablated any AO contribution to metabolism. Putative back-up compounds in this novel series provided increased sp 3 character, uniform CYP 450 -mediated metabolism across species, good functional potency and high CNS penetration. Key to the optimization was a combination of matrix and iterative libraries that allowed rapid surveillance of multiple domains of the allosteric ligand.
AB - This letter describes the further chemical optimization of VU0424238 (auglurant), an mGlu 5 NAM clinical candidate that failed in non-human primate (NHP) 28 day toxicology due to accumulation of a species-specific aldehyde oxidase (AO) metabolite of the pyrimidine head group. Here, we excised the pyrimidine moiety, identified the minimum pharmacophore, and then developed a new series of saturated ether head groups that ablated any AO contribution to metabolism. Putative back-up compounds in this novel series provided increased sp 3 character, uniform CYP 450 -mediated metabolism across species, good functional potency and high CNS penetration. Key to the optimization was a combination of matrix and iterative libraries that allowed rapid surveillance of multiple domains of the allosteric ligand.
KW - CNS
KW - Metabotropic glutamate receptor
KW - Negative allosteric modulator (NAM)
KW - Structure-Activity Relationship (SAR)
KW - mGlu
UR - http://www.scopus.com/inward/record.url?scp=85056617861&partnerID=8YFLogxK
U2 - 10.1016/j.bmcl.2018.11.017
DO - 10.1016/j.bmcl.2018.11.017
M3 - Article
VL - 29
SP - 47
EP - 50
JO - Bioorganic and Medicinal Chemistry Letters
JF - Bioorganic and Medicinal Chemistry Letters
SN - 0960-894X
IS - 1
ER -