کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
10592512 | 981794 | 2012 | 5 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
4-(1-Phenyl-1H-pyrazol-4-yl)quinolines as novel, selective and brain penetrant metabotropic glutamate receptor 4 positive allosteric modulators
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کلمات کلیدی
موضوعات مرتبط
مهندسی و علوم پایه
شیمی
شیمی آلی
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
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 (LEÂ =Â 0.43), optimization of in vitro potency for this series reached a plateau around EC50Â =Â 200Â nM.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Bioorganic & Medicinal Chemistry Letters - Volume 22, Issue 9, 1 May 2012, Pages 3235-3239
Journal: Bioorganic & Medicinal Chemistry Letters - Volume 22, Issue 9, 1 May 2012, Pages 3235-3239
نویسندگان
Hermogenes N. Jimenez, Kevin G. Liu, Sang-Phyo Hong, Michael S. Reitman, Michelle A. Uberti, Maria D. Bacolod, Manuel Cajina, Megan Nattini, Michael Sabio, DarÃo Doller,