4-(1-Phenyl-1H-pyrazol-4-yl)quinolines as novel, selective and brain penetrant metabotropic glutamate receptor 4 positive allosteric modulators
| Autor: | Manuel Cajina, Megan Nattini, Michael Sabio, Michael S. Reitman, Dario Doller, Kevin G. Liu, Maria D. Bacolod, Hermogenes N. Jimenez, Sang-Phyo Hong, Michelle A. Uberti |
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| Rok vydání: | 2012 |
| Předmět: |
Allosteric modulator
Stereochemistry Clinical Biochemistry Allosteric regulation Drug Evaluation Preclinical Pharmaceutical Science Pyrazole Receptors Metabotropic Glutamate Biochemistry Structure-Activity Relationship chemistry.chemical_compound Allosteric Regulation Drug Discovery Animals Molecular Biology Ligand efficiency Metabotropic glutamate receptor 4 Organic Chemistry Quinoline Brain Hit to lead Rats chemistry Lipophilicity Quinolines Molecular Medicine |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 22:3235-3239 |
| ISSN: | 0960-894X |
| Popis: | 4-(1-Phenyl-1H-pyrazol-4-yl)quinoline (1) was identified by screening the Lundbeck compound collection, and characterized as having mGlu4 receptor positive allosteric modulator properties. Compound 1 is selective over other mGlu receptors and a panel of GPCRs, ion channels and enzymes, but has suboptimal lipophilicity and high plasma and brain non-specific binding. In view of the challenges at the hit-to-lead stage previously reported in the development of mGlu4 receptor positive allosteric modulators (PAMs), a thorough structure-mGlu4 PAM activity relationship study was conducted to interrogate the chemical tractability of this chemotype. The central pyrazole ring tolerates the addition of one or two methyl groups. The C-7 position of the quinoline ring provides a site tolerant to hydrophilic substituents, enabling the design of diverse analogs with good in vitro mGlu4 PAM potency and efficacy, as well as improved microsomal turnover in vitro, compared to 1. In spite of the excellent ligand efficiency of 1 (LE = 0.43), optimization of in vitro potency for this series reached a plateau around EC50 = 200 nM. |
| Databáze: | OpenAIRE |
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