کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
10585934 | 981382 | 2011 | 10 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Conformationally restricted analogs of the direct thrombin inhibitor FM 19
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کلمات کلیدی
OICtert-butoxycarbonylHBTUN-methyl-2-pyrrolidoneDIEANMPFluorenylmethyloxycarbonylBOCFMOCSARHOBtDTITFATHFN,N-diisopropylethylamine - N، N-دییزوپروپیلتیلامینTrifluoroacetic acid - اسید TrifluoroaceticTetrahydrofuran - تتراهیدروفورانPar - توسطStructure–activity relationships - روابط ساختاری-فعالیتPeptide synthesis - سنتز پپتیدStructure-based design - طراحی مبتنی بر ساختارdirect thrombin inhibitor - مستقیم مهار کننده ترومبینthrombin inhibitor - مهار کننده ترومبینhydroxybenzotriazole - هیدروکسی بنزوتریازولprotease-activated receptor - گیرنده پروتئاز فعال
موضوعات مرتبط
مهندسی و علوم پایه
شیمی
شیمی آلی
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
The serine protease thrombin plays several key roles in the clotting cascade within the hemostatic system, such as in fibrin formation and platelet activation. Thus, development of an inhibitor that binds to the enzyme's active site (a direct thrombin inhibitor) offers an approach for the treatment of thrombus-associated diseases. Previous structure-activity relationship studies originally based on the bradykinin breakdown product Arg-Pro-Pro-Gly-Phe (RPPGF) led to the development of lead compound FM 19 (d-Arg-Oic-Pro-d-Ala-Phe(p-Me)-NH2). The recently determined X-ray structure of FM 19 in the active site of thrombin has revealed sites of modification to potentially improve inhibition. In this study, we report the synthesis and biological characterization of nine peptides that replace only the d-Arg residue of the FM 19 sequence, investigating ways to add conformational restriction, modification of the basic moiety at the end of the side chain, and removal of the charge from the N-terminus. Two of these peptides, 6 and 7 (IC50 values of 0.51 and 0.45 μM, respectively), show similar potency to the best compounds in the FM 19 series reported thus far.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Bioorganic & Medicinal Chemistry - Volume 19, Issue 24, 15 December 2011, Pages 7425-7434
Journal: Bioorganic & Medicinal Chemistry - Volume 19, Issue 24, 15 December 2011, Pages 7425-7434
نویسندگان
Elizabeth A. Girnys, Vanessa R. Porter, Henry I. Mosberg,