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Synthesis and SAR of a series of mGlu7 NAMs based on an ethyl-8-methoxy-4-(4-phenylpiperazin-1-yl)quinoline carboxylate core
- Source :
- Bioorganic & Medicinal Chemistry Letters. 30:127529
- Publication Year :
- 2020
- Publisher :
- Elsevier BV, 2020.
-
Abstract
- A High-Throughput Screening (HTS) campaign identified a fundamentally new mGlu7 NAM chemotype, based on an ethyl-8-methoxy-4-(4-phenylpiperazin-1-yl)quinolone carboxylate core. The initial hit, VU0226390, was a potent mGlu7 NAM (IC50 = 647 nM, 6% L-AP4 min) with selectivity versus the other group III mGlu receptors (>30 μM vs. mGlu4 and mGlu8). A multi-dimensional optimization effort surveyed all regions of this new chemotype, and found very steep SAR, reminiscent of allosteric modulators, and unexpected piperazine mimetics (whereas classical bioisosteres failed). While mGlu7 NAM potency could be improved (IC50s ~ 350 nM), the necessity of the ethyl ester moiety and poor physiochemical and DMPK properties precluded optimization towards in vivo tool compounds or clinical candidates. Still, this hit-to-lead campaign afforded key medicinal chemistry insights and new opportunities.
- Subjects :
- Chemotype
010405 organic chemistry
Stereochemistry
Organic Chemistry
Clinical Biochemistry
Allosteric regulation
Quinoline
Pharmaceutical Science
Ethyl ester
01 natural sciences
Biochemistry
0104 chemical sciences
010404 medicinal & biomolecular chemistry
chemistry.chemical_compound
Piperazine
chemistry
Drug Discovery
Molecular Medicine
Moiety
Carboxylate
Selectivity
Molecular Biology
Subjects
Details
- ISSN :
- 0960894X
- Volume :
- 30
- Database :
- OpenAIRE
- Journal :
- Bioorganic & Medicinal Chemistry Letters
- Accession number :
- edsair.doi...........c3d6a1ca44e2fb133fb20d22f5597e3b