کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
10594161 981818 2011 4 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
N-Heteroaryl glycinamides and glycinamines as potent NPY5 antagonists
موضوعات مرتبط
مهندسی و علوم پایه شیمی شیمی آلی
پیش نمایش صفحه اول مقاله
N-Heteroaryl glycinamides and glycinamines as potent NPY5 antagonists
چکیده انگلیسی
Subtype specific ligands are needed to evaluate the therapeutic potential of modulating the brain's neuropeptide Y system. The benzothiazepine glycinamide 1a was identified as an NPY5 antagonist lead. While having acceptable solubility, the compound was found to suffer from high clearance and poor exposure. Optimization efforts are described targeting improvements in potency, microsomal stability, and PK properties. The low microsomal stability and poor PK properties were addressed through the optimization of the sulfonyl urea and replacement of the benzothiazepinone with other N-heteroaryl glycinamides. For example, the analogous benzoxazine glycinamide 2e has improvements in both affinity (human Y5 Ki 4 nM vs 1a 27 nM) and microsomal stability (human CLint 2.5 L/min vs 1a 35 L/min). However the brain penetration (B/P 43/430 nM at 10 mg/kg PO) remained an unresolved issue. Further optimization by decreasing the hydrogen bond donating properties and PSA provided potent and brain penetrant NPY5 antagonists such as 5f (human Y5 Ki 9 nM, B/P 520/840 nM 10 mg/kg PO).
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Bioorganic & Medicinal Chemistry Letters - Volume 21, Issue 18, 15 September 2011, Pages 5573-5576
نویسندگان
, , , , , , , , , , ,