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Discovery and characterization of N-(1,3-dialkyl-1H-indazol-6-yl)-1H-pyrazolo[4,3-b]pyridin-3-amine scaffold as mGlu4 positive allosteric modulators that mitigate CYP1A2 induction liability
- Source :
- Bioorganic & Medicinal Chemistry Letters. 28:2641-2646
- Publication Year :
- 2018
- Publisher :
- Elsevier BV, 2018.
-
Abstract
- Previous reports from our laboratory disclosed the structure and activity of a novel 1H-pyrazolo[4,3-b]pyridine-3-amine scaffold (VU8506) which showed excellent potency, selectivity and in vivo efficacy in preclinical rodent models of Parkinson’s disease. Unfortunately, this compound suffered from significant CYP1A2 induction as measured through upstream AhR activation (125-fold) and thus was precluded from further advancement in chronic studies. Herein, we report a new scaffold developed recently which was systematically studied in order to mitigate the CYP1A2 liabilities presented in the earlier scaffolds. We have identified a novel structure that maintains the potency and selectivity of other mGlu4 PAMs, leading to 9i (hmGlu4 EC50 = 43 nM; AhR activation = 2.3-fold).
- Subjects :
- 0301 basic medicine
Scaffold
Chemistry
Stereochemistry
Organic Chemistry
Clinical Biochemistry
Allosteric regulation
CYP1A2
Pharmaceutical Science
Biochemistry
03 medical and health sciences
030104 developmental biology
0302 clinical medicine
In vivo
Drug Discovery
Molecular Medicine
Potency
Amine gas treating
Selectivity
Molecular Biology
030217 neurology & neurosurgery
Subjects
Details
- ISSN :
- 0960894X
- Volume :
- 28
- Database :
- OpenAIRE
- Journal :
- Bioorganic & Medicinal Chemistry Letters
- Accession number :
- edsair.doi...........390fa423031667d09c5d2e8b4064d1d9