24. Yan+PHAR+7334+Antiplatelet+and+Fibronolytic+Medicinal+Chemistry.pdf

PHAR 7334 Medicinal Chemistry of Antiplatelet and fibrinolytic medication Liang-Jun Yan, Ph.D. Department of Pharmaceutical Sciences University of North Texas Health Science Center Learning objectives 1. Being able to recognize the chemical structures of commonly seen antiplatelet and fibrinolyt...

PHAR 7334 Medicinal Chemistry of Antiplatelet and fibrinolytic medication Liang-Jun Yan, Ph.D. Department of Pharmaceutical Sciences University of North Texas Health Science Center Learning objectives 1. Being able to recognize the chemical structures of commonly seen antiplatelet and fibrinolytic agents; 2. Being able to explain structure-activity relationship of different drugs; 3. Describe how chemical modifications may affect the potency and toxicity of therapeutic agents; 4. Being able to predict or comment on the potential therapeutic or toxicity responses of existing or novel agents based on their chemical/structural information. Hemostasis The cessation of blood loss from a damaged vessel (Stop bleeding) primary hemostasis -platelet plug formation secondary hemostasis -formation of insoluble, cross-linked fibrin We cannot live without hemostasis, and we cannot live with too much hemostasis either Anti-platelet medications Aspirin and Triflusal (salicylic acid derivatives) salicylic acid Leading to acetylation of COX1 Aspirin (acetyl-salicylic acid) Irreversibly inhibits cyclooxygenase COX1 (needed for PGH2 synthesis) and further block thromboxane A2 (TXA2) production Leading to inhibition of NF-κB and the downregulation of VCAM1 in endothelium Deacetylated triflusal still retains significant antiplatelet effects, due to COX1-independent mechanisms (e.g., increasing cAMP in platelets and downregulation of VCAM1 in endothelium) VCAM1= vascular cell adhesion molecule-1 Triflusal (trifluoromethylated aspirin) Less risk for hemorrhagic complications Dipyridamole and Cilostazol (phosphodiesterase inhibitors) Converting cAMP into AMP (High level of cAMP in platelets leads to reduced activation of platelets) Dipyridamole Cilostazol Suppressing cAMP degradation in platelets (reducing platelet aggregation) Thienopyridines (P2Y purinergic receptor inhibitors) Ticlopidine Clopidogrel Prasugrel Active metabolites of Ticlopidine and Clopidogrel active metabolite toxic metabolites (ammonium cation) CYP3A4 thiolactone hydrolysis thiolactone active metabolite Activity is dependent on the free –SH group. No free –SH group, not active. Active metabolite of Prasugrel Prasugrel thiolactone hydrolysis (S-methylation) active metabolite inactive metabolite Again, free –SH group is needed for activity Glycoprotein Ilb/Illa receptor antagonists Peptides containing Arg-Gly-Asp (RGD) or Lys-Gly-Asp (KGD) sequence can bind to the glycoprotein llb/llla receptor Lys-Gly-Asp (KGD) Pharmacophore Eptifibatide (reversible blocker) Note the amino group and the carboxyl group end Chemical structures that mimic the distance between carboxyl and amine groups of KGD sequence can block the glycoprotein llb/llla receptor (KGD=lysine-glycine-aspartate) Note the amino group and the carboxyl group end Tirofiban (non-peptide reversible blocker) Chemical structures that mimic the distance between carboxyl and amine groups of KGD sequence can block the glycoprotein llb/llla receptor Lamifiban (non-peptide reversible blocker) Note the amino group and the carboxyl group end Antibody can bind to the glycoprotein llb/llla receptor Protease-activated receptor (PAR-1) antagonists Himbacine (an alkaloid isolated from the bark of Australian magnolias) Vorapaxar (PAR-1 inhibitor) Fibrinolytic medications This is how blood clotting gets removed in the body….. Serine protease In addition to tissue plasminogen activator (t-PA), kinins, urokinase-type plasminogen activator (uPA), and streptokinase (a bacterial plasminogen activator) can cleave plasminogen to generate plasmin. FDP= fibrin degraded products Thrombolytic agents (serine protease) Streptokinase (not available in US), Urokinase: non-selectively digest free plasminogen and plasminogen bound to fibrin Alteplase (t-PA): fibrin-bound plasminogen specific, low reactivity with free plasminogen Alteplase Reteplase (r-PA): lacking amino acids 1 to 172 in alteplase, fibrin specific, with longer half life in human body due to the reduced hepatic elimination Alteplase Reteplase Tenecteplase (TNK-tPA)-the product of alteplase with the genetically engineered substitutions of T103N (threonine 103 replaced by asparagine), N117Q (asparagine 117 replaced by glutamine), and amino acids 296 to 299 where lysine (K)-histidine-arginine-arginine are replaced by four alanine residues. Fibrin-bound plasminogen specific and resistant to the endogenous inhibitor of t-PA. Tenecteplase