5.4 MedChem

Thrombus (blood clot) consists of?

aggregated platelets + red blood cells + a mesh of cross-linked fibrin protein.

Diseases that involve a thrombotic condition?

Acute myocardial infarction

Valvular heart disease

Unstable angina

Atrial fibrillation

Surgical procedures

Contact activation pathway (intrinsic; used for maintenance of homeostasis)

involves sequential activation of factors FXII, FXI, and FIX.

Tissue factor (TF) pathway (extrinsic; caused by trauma)

TF glycoprotein is a major initiating factor of arterial thrombogenesis

Which are the 2 classes of oral anticoagulants?

Coumarin derivatives

1,3-Indandiones (rarely used clinically due to toxicities)

MOA of Coumarins: ________ converts glutamic acid (Glu) of Factors II, VII, IX, and X to ___________, which chelates Ca²⁺ to activate these factors.

γ-Glutamyl carboxylase (GGCX)

Gla (γ-carboxyglutamic acid)

Coumarin

Warfarin

___ is a cofactor of GGCX and is oxidized to vitamin K epoxide (KO).

KH₂

________ converts KO back to vitamin K and KH₂.

VKOR (vitamin K epoxide reductase)

Coumarin derivatives inhibit VKOR acting as ________

vitamin K antagonists

All coumarin derivatives are __________

water-insoluble lactones

For coumarin derivatives substitutions often occur on the __________

lactone ring (positions 3 and 4)

For coumarin derivatives the _______ makes the drug weakly acidic and allows the formation of ____________

4-OH group; water-soluble sodium salts

Warfarin is a racemic mix, ________ isomer being more potent than _______

S>R

Thrombin is a _________ converting fibrinogen → fibrin, catalyzing many coagulation reactions.

serine protease

Thrombin is the _______ of coagulation and amplifies its own production.

central effector

_____ is a naturally occurring anticoagulant preventing formation and extension of blood clots.

Heparin

Heparin is composed of _________ with alternating ____ and ______

- sulfated polysaccharides (5-30 kDa)

- N-acetyl-D-glucosamine

- uronic acid

mucopolysaccharides (MW 5-30 kDa, mean 15 kDa)

HMWH (unfractionated heparin)

4-6 kDa; selective, with improved PK/PD

LMWH (low molecular weight heparin)

Which are examples of LMWH?

Ardeparin, Dalteparin, Enoxaparin, Tinzaparin

Synthetic, highly sulfonated pentasaccharide; selective and improved PK.

Fondaparinux

MOA of Heparins: ________ inhibits clotting factors IIa, IXa, Xa, XIa, and XIIa by forming stable complexes.

Antithrombin (AT) III

MOA: Heparin binds AT-III, which causes a ____ and enhances its action 2000-fold

conformational change

LMWH predominantly inhibit _________

factor Xa

Which are the 3 Thrombin binding sites?

Exosite I (E1): fibrin binding site

Exosite II (E2): heparin binding site

Active site: flanked by 60- and γ-loops

Univalent DTIs

bind the active site

Bivalent DTIs

bind both E1 and the active site

Which are approved DTIs?

Hirudin (1909, not available)

Lepirudin (discontinued 2012)

Desirudin (2003)

Bivalirudin (2000)

Argatroban (2000)

Dabigatran etexilate (2010)

Small 65-AA protein from Hirudo medicinalis (leech)

Hirudin

Hirudin forms ________ with thrombin (ionic C-terminal interaction).

1:1 complex

Hirudin inactivates ____________

free and fibrin-bound thrombin.

Unlike heparin, DTIs _______ bind thrombin (no ATIII cofactor needed).

directly and reversibly

DTIs inhibit _______ (heparin inhibits IIa, IXa, Xa, XIa, XIIa).

only thrombin

Lepirudin and Desirudin:

- Bivalent DTIs binding active site + exosite I (E1).

- Nearly irreversible inhibition.

- Inhibit both free and fibrin-bound thrombin.

________ is a peptidomimetic that binds selectively to thrombin catalytic site (univalent, competitive).

Argatroban

Which Argatroban isomer is more potent?

S>R

Argatroban is a _________ of both free and clot-bound thrombin.

reversible inhibitor

Argatroban

Orally active prodrug of dabigatran (nonpeptidomimetic).

Dabigatran Etexilate

Dabigatran Etexilate

Reversible, benzamidine-based DTI, that binds to S1, S2, and partially S4 sites.

Dabigatran Etexilate

A. S2

B. S4

C. S1

Antiplatelet drugs focus on:

COX-1 inhibitors

PDE-3 inhibitors

P2Y receptor antagonists

GPIIb/IIIa receptor antagonists

COX-1 Inhibitors ______ induces platelet aggregation.

TXA₂

______ irreversibly acetylates COX-1 → blocks TXA₂ → inhibits aggregation for platelet lifetime.

Aspirin

Aspirin

_____ converts cAMP → AMP in platelets/vessels.

PDE3

PDE3 Inhibitors ______ → inhibit platelet aggregation + vasodilate.

↑ cAMP

Selective quinolinone derivative targeting PDE3A.

Cilostazol

Cilostazol

A. Prasugrel

B. Clopidogrel

C. Ticlopidine

P2Y1 and P2Y12 are activated by _______.

ADP

Ticlopidine, clopidogrel, and prasugrel are _________, which exhibit selective, ________ inhibition of ADP-induced platelet aggregation.

thienopyridines

irreversible

Thienopyridines are ____, and the ___ binds irreversibly to P2Y12 by forming a___________ in P2Y12, therefore blocking the binding of the agonist.

- prodrugs

- thiol

- disulfide bridge to a cysteine

Ticagrelor and Cangrelor are two _________ inhibitors of P2Y12.

reversible

Ticagrelor (Brilinta)

Cangrelor (Kengreal)

Ticagrelor binds reversibly to P2Y12 at a site distinct from the ADP-binding site and inhibits ADP signaling and receptor conformational change by ___________; ADP can still bind at its binding site.

"locking" the receptor in an inactive state

___________ have been developed to prevent fibrinogen binding and cross-linking, thereby inhibiting platelet aggregation.

GPIIb/IIIa receptor antagonists

The natural binding ligands for the GPIIb/IIIa receptor contain the _________ sequence.

Arg-Gly-Asp (RGD)

Which are the GPIIb/IIIa receptor antagonists available?

1. monoclonal antibodies {Arg-Gly-Asp (RGD) sequence]

2.synthetic peptides containing either the RGD or Lys-Gly-Asp (KGD) sequences

3. peptidomimetic & nonpeptide RGD mimetics.