Coagulation_Desai - Coagulation and Anticoagulation MEDC...

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Unformatted text preview: Coagulation and Anticoagulation MEDC 310 Umesh R. Desai, Ph.D. Department of Medicinal Chemistry & Institute f Structural Biology and Drug Discovery I i for S l Bi l dD Di 828-7328 [email protected] urdesai MEDC 310 1 Clotting Why? Wh ? How? When? Where? h MEDC 310 2 What is a Blood Clot? MEDC 310 3 The Clotting Process A) Physical Process aspirin B) Chemical Process antithrombins Wound platelet activation Wound factor Xa fibrinogen release l of ADP A2 th thrombin bi generation release of l f thromboxane thrombin fibrin (monomers) prothrombin Further activation of platelets ADP receptor antagonists GP IIb-IIIa receptor antagonists vitamin K-dependent -carboxylation of carboxylation Glu residues Platelet aggregation fibrin (polymer) coumarins CLOT Taken from Desai UR (2004) Med. Res. Rev. 24, 151-181. MEDC 310 4 Physical Process of Clotting injured i i j d tissue exposure of f subendothelial cells vasoconstriction i i blood subendothelial cells platelets platelets adhere to exposed cells platelets aggregate and form a "plug" MEDC 310 5 The Coagulation Cascade XI XII HMWK XIIa IX XIa PL/Ca2+ X IXa VIII IIa II VIIIa II V IIa Xa Va Xa VIIa PL/Ca2+ F IIa Fm XIIIa IIa XIII CLOT VII TF PL/Ca2+ MEDC 310 6 Interesting Features of the Coagulation Cascade Catalysis and Specificity of Reactions Involved in the Cascade MEDC 310 7 Interesting Features of the Coagulation Cascade Polymerization MEDC 310 8 Interesting Features of the Coagulation Cascade Amplification C E1 A E2 E3 F E4 D E3 G G X Y E1 A B E2 F E4 C D MEDC 310 9 Regulation of Coagulation XI XII HMWK XIIa IX XIa PL/Ca2+ X IXa VIII APC IIa II VIIIa II F IIa Fm AT Why Regulate Clotting? V IIa Xa Va Xa VIIa PL/Ca2+ TM:IIa Protein C VII TF PL/Ca2+ XIIIa IIa CLOT TFPI MEDC 310 XIII 10 Inhibitors of Clotting (Anticoagulants) Natural Anticoagulants Antithrombin, Tissue Factor Pathway Inhibitor, Protein C N t Natural P d t d i d Anticoagulant D l Product-derived A ti l t Drugs Heparin-based anticoagulants, e.g., heparin, low molecular weight heparin, fondaparinux, idraparinux Coumarin-based anticoagulants, e.g., warfarin, acenocoumarin Hirudin (derived from leeches), lepirudin, desirudin, bivalirudin Tick anticoagulant peptide Other Anticoagulants Argatroban, melagatran Argatroban melagatran, ximelagatran MEDC 310 11 Inhibitors of Coagulation Structure and sequence _ CH2OSO3 O OH O _ O OH OH O COO _ CH2OH O OH _ O _ O COO OH OSO3 _ O _ CH2OSO3 O OH O NHCOCH3 OH _ _ O COO OH O _ CH2OSO3 O OH _ NHSO3 O NHSO3 NHSO3 polymeric structure of heparin 6 CH2OH O 1 2 4 5 _ O 6 COO 1 4 6 COO 5 4 5 O 1 2 OH OH 2 OH O3 NH2 -D-glucosamine O3 O3 OH -L-iduronic acid OH -D-glucuronic acid MEDC 310 12 Pentasaccharide _ CH2OSO3 O OH O NHSO3 _ O COO _ CH2OSO3 O _ OSO3 O _ O _ COO OH _ O OSO3 _ O _ CH2OSO3 O OH _ NHSO3 O OH OH NHSO3 MEDC 310 13 Clinically useful coumarins and 1,3-indanediones 1,3O O * O CH3 O OH O O O OH OH warfarin * chiral center O H bishydroxycoumarin (dicoumarol) OMe O Anisidione (2-(p-methoxyphenyl)-1,3--indandione MEDC 310 14 Direct Thrombin Inhibitors HIRUDIN Isolated from leech, hirudino medicinalis. A polypeptide consisting of 65 amino acid residues that binds thrombin in the active site as well as another site called exosite I H2N-D-Phe-Pro-Arg-Pro-Gly-Gly-Gly-Gly-Asn-Gly HOOC-Leu-Tyr-Glu-Glu-Pro-Ile-Glu-Glu-Phe-Asp Bivalirudin H3C O S H O N H N O COOH CH3 NH Argatroban H2N O RO O NH O N H N O N O H N R' NH2 RO N N N N R' N N H CH3 NH2 Ximelagatran R = -CH2CH3; R' = -OH Melagatran R = -H; R' = -H Dabigatran etexilate R = -CH2CH3; R' = -COO-nC6H13 Dabigatran R = -H; R' = -H Figure 2. Structures of direct thrombin inhibitors (DTIs). Shaded oval represents the guanidine or amidine group that mimics the arginine side chain of the P 1 residue recognized by thrombin. P-1 MEDC 310 15 All Anticoagulants have Significant Problems!! Our work .... designing molecules that are radically different from all known anticoagulants using a multidisciplinary approach involving computational chemistry, organic synthesis, enzyme assays, mechanistic biochemistry, and p y y , y, plasma, blood , and animal studies ... MEDC 310 16 ...
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