Discovery and development of direct thrombin inhibitors

Add links
Source: Wikipedia, the free encyclopedia.

Direct thrombin inhibitors (DTIs) are a class of

factor Xa inhibitors, or even dual thrombin and fXa inhibitors that have a broader mechanism of action by both inhibiting factor IIa (thrombin) and Xa. A recent review of patents and literature on thrombin inhibitors has demonstrated that the development of allosteric and multi-mechanism inhibitors might lead the way to a safer anticoagulant.[1]

History

Hirudo medicinalis

Vitamin K antagonists are the most commonly used oral anticoagulants today and warfarin was the 11th most prescribed drug in the United States in 1999[3] and is actually the most widely prescribed oral anticoagulant worldwide.[6] Warfarin has its disadvantages though, just like heparin, such as a narrow therapeutic index and multiple food and drug interactions and it requires routine anticoagulation monitoring and dose adjustment.[4][7] Since both heparin and warfarin have their downsides the search for alternative anticoagulants has been ongoing and DTIs are proving to be worthy competitors. The first DTI was actually hirudin, which became more easily available with genetic engineering. It is now available in a recombinant form as lepirudin (Refludan) and desirudin (Revasc, Iprivask). Development of other DTIs followed with the hirudin analog, bivalirudin, and then the small molecular DTIs.[4] However, such DTIs were also having side effects such as bleeding complications and liver toxicity, and their long-term effects were in doubt.[citation needed
]

Mechanism of action

Blood clotting cascade

Coagulation cascade

When a

drug target for anticoagulant drugs such as heparin, warfarin and DTIs and antiplatelet drugs like aspirin.[8][10][11]

Binding sites

Thrombin is in the

exosites (1 and 2). Thrombin is a little different from other serine proteases as exosite 1 is anion-binding and binds to fibrin and other similar substrates while exosite 2 is a heparin-binding domain.[8][9]

DTIs inhibition

Thrombin has three binding sites; the active site, exosite 1 and exosite 2. Drugs can either bind to both the active site and exosite 1 (bivalent) or just to the active site (univalent)

.

DTIs inhibit thrombin by two ways;

prophylaxis as well as treatment for embolisms/clots.[8][10]

Active site's pockets

Dabigatran chemical structure with binding pockets highlighted S1(red), S2 (green) and S4 (blue)

DTIs that fit in the active binding site have to fit in the hydrophobic pocket (S1) that contains aspartic acid residue at the bottom which recognizes the basic side chain. The S2 site has a loop around tryptophan which occludes a hydrophobic pocket that can recognize larger aliphatic residues. The S3 site is flat and the S4 site is hydrophobic, it has tryptophan lined by leucine and isoleucine.[9]

Chemical structure of NAPAP

Nα-(2-naphthyl-sulphonyl-glycyl)-DL-p-amidinophenylalanyl-piperidine (NAPAP) binds thrombin in the S1, S2 and S4 pockets. The amidine group on NAPAP forms a bidentate salt bridge with Asp deep in the S1 pocket, the piperidine group takes the role of proline residue and binds in the S2 pocket, and the naphthyl rings of the molecule forms a hydrophobic interaction with Trp in the S4 pocket. Pharmaceutical companies have used the structural knowledge of NAPAP to develop DTIs. Dabigatran, like NAPAP binds to S1, S2 and S4 pockets. Benzamidine group on the dabigatran structure binds deep in the S1 pocket, the methylbenzimidazole fits nicely in the hydrophobic S2 pocket and the Ile and Leu at the bottom of the S4 pocket binds to the aromatic group of dabigatran.[9]

Drug development

Hirudin derivatives

Hirudin in complex with thrombin

Hirudin

extravascular compartment and only 20% is found in the plasma. The most common desulfatohirudins today are lepirudin and desirudin.[15]

Hirudin

In a

randomized trials involving hirudin and other DTIs versus heparin in the treatment of acute coronary syndrome (ACS) it was found that hirudin has a significantly higher incidence of bleeding compared with heparin. Hirudin is therefore not recommended for treatment of ACS and currently it has no clinical indications.[4]

Lepirudin

Lepirudin amino acids sequence

Lepirudin is approved for the treatment of

prospective studies, called the Heparin-Associated-Thrombocytopenia (HAT) 1,2, and 3, were performed that compared lepirudin with historical controls in the treatment of HIT. All three studies showed that the risk of new thrombosis was decreased with the use of lepirudin, but the risk for major bleeding was increased.[15] The higher incidence of major bleeding is thought to be the result of an approved dosing regimen that was too high, consequently the recommended dose was halved from the initial dose.[4]
As of May 2012 Bayer HealthCare, the only manufacturer of lepirudin injections, discontinued its production. They expect supplies from wholesalers to be depleted by mid-2013.[17]

Desirudin

Desirudin is approved for treatment of

enoxaparin (a LMWH) or unfractionated heparin have been performed. In both studies desirudin was considered to be superior in preventing VTE. Desirudin also reduced the rate of proximal deep vein thrombosis. Bleeding rates were similar with desirudin and heparin.[4][8]

Bivalirudin

Chemical structure of the polypeptide Bivalirudin

hepatic metabolism and proteolysis also contribute to its metabolism, making it safer to use in patients with renal impairment; however, dose adjustments are needed in severe renal impairment.[8][16]

Small molecular direct thrombin inhibitors

Small molecular direct thrombin inhibitors (smDTIs) are non-peptide small molecules that specifically and reversibly inhibit both free and clot-bound thrombin by binding to the active site of the thrombin molecule. They prevent VTE in patients undergoing hip- and knee replacement surgery.[10] The advantages of this type of DTIs are that they do not need monitoring, have a wide therapeutic index and the possibility of oral administration route. They are theoretically more convenient than both vitamin K antagonist and LMWH. Researches will, however, have to show the indication of the use and their safety.[18]

The smDTIs where derived using a peptidomimetic design with either P1 residue from arginine itself (e.g. argatroban) or arginine-like substrates such as benzamidine (e.g. NAPAP).[9]

Argatroban

Chemical structure of argatroban showing where it binds to the S1 and S2 pockets

hepatic impairment but not renal damage. Argatroban has been approved in the USA since 2000 for the treatment of thrombosis in patients with HIT and 2002 for anticoagulation in patients with a history of HIT or are at risk of HIT undergoing percutaneous coronary interventions (PCI).[10][19] It was first introduced in Japan in 1990 for treatment of peripheral vascular disorders.[19]

Ximelagatran

The publication of the NAPAP-fIIa

FDA.[20]

The double prodrug ximelagatran turns into the active form melagatran in vivo.

Dabigatran etexilate

Researchers at

absorbed, it lacks interaction with cytochrome P450 enzymes and with other food and drugs, there is no need for routine monitoring and it has a broad therapeutic index and a fixed-dose administration, which is excellent safety compared with warfarin.[4] Unlike ximelagatran, a long-term treatment of dabigatran etexilate has not been linked with hepatic toxicity, seeing as how the drug is predominantly eliminated (>80%) by the kidneys. Dabigatran etexilate was approved in Canada and Europe in 2008 for the prevention of VTE in patients undergoing hip- and knee surgery. In October 2010 the US FDA approved dabigatran etexilate for the prevention of stroke in patients with atrial fibrillation (AF).[6][10] Many pharmaceutical companies have attempted to develop orally bioavailable DTI drugs but dabigatran etexilate is the only one to reach the market.[9]

In a 2012 meta-analysis dabigatran was associated with increased risk of myocardial infarction (MI) or ACS when tested against different controls in a broad spectrum of patients.[22]

The double prodrug Dabigatran etexilate turns into the active form Dabigatran in vivo

Table 1: Summary of characteristics of DTIs

Bivalent/ Univalent[4] Route of administration[10] Metabolism[10] Binding to active site and/or exosite 1[4] Indications Limitations Advantages
Native Hirudin B (Parenteral) Has no indications
Lepirudin B Parenteral (iv/sc) Renal Irreversible Prevention of further thrombosis in patients with HIT[16] Narrow TI, potential increased bleedings, antihirudid antibodies are formed in 40% of patients, need for weight-based dosing[10]
Desirudin
 B Parenteral (iv/sc) Renal Irreversible Europe: treatment of VTE[4] USA: Prevention of DVT in patients undergoing hip replacement surgery[23] Less need for weight-based doses and routine monitoring compared to lepirudin because of sc administration[10]
Bivalirudin B Parenteral (iv) Proteolytic cleavage, hepatic, 20% renal Reversible Prevention of acute ischemic complications in patients with unstable angina and with or at risk of HIT undergoing PTCA or PCI[24] Dose adjustments are needed in severe renal impairment[16] Decreased bleeding risk due to reversible binding,[4] improved safety profile compared with r-hirudins, fast onset of action[10]
Argatroban U Parenteral (iv) Hepatical, mostly biliary Reversible Prevention and treatment of thrombosis in patients with HIT[10] No bolus dose needed[10]
Ximelagatran U Oral Hepatic Reversible Europe: Prevention of VTE[10]

USA: FDA never gave approval[20]

Long-term therapy (›35 days) is associated to hepatotoxicity – taken off market in Europe[18]
Dabigatran etexilate
 U Oral Primarily renal, remainder is conjugated with glucuronic acid in liver Reversible Prevention of stroke and embolism in patients with AF[25] Rapid onset of action, lack of interaction with CYP450, food or drugs, broad TI, fixed dose administration and good safety profile, not associated with hepatotoxicity for long-term use[10]

iv: intravenous, sc: subcutaneous, HIT: heparin-induced thrombocytopenia, VTE: Venous thromboembolism, DVT: Deep vein thrombosis, PTCA: Percutaneous transluminal coronary angioplasty, PCI: percutaneous coronary intervention, FDA: Food and Drug Administration, AF: Atrial fibrillation, TI: Therapeutic index

Status 2014

In 2014 dabigatran remains the only approved oral DTI

direct factor Xa inhibitors, but there is one DTI called AZD0837,[26] which is a follow-up compound of ximelgatran that is being developed by AstraZeneca. It is the prodrug of a potent, competitive, reversible inhibitor of free and fibrin-bound thrombin called ARH0637.[18] The development of AZD 0837 is discontinued. Due to a limitation identified in long-term stability of the extended-release AZD0837 drug product, a follow-up study from ASSURE on stroke prevention in patients with non-valvular atrial fibrillation, was prematurely closed in 2010 after 2 years. There was also a numerically higher mortality against warfarin.[27][28][29] In a Phase 2 trial for AF the mean serum creatinine concentration increased by about 10% from baseline in patients treated with AZD0837, which returned to baseline after cessation of therapy.[30] Development of other oral DTIs, such as Sofigatran from Mitsubishi Tanabe Pharma has been discontinued.[26]
Another strategy for developing oral anticoagulant drugs is that of dual thrombin and fXa inhibitors that some pharmaceutical companies, including Boehringer Ingelheim, have reported on. These compounds show favorable anticoagulant activity in vitro.[9]

See also

References

  1. S2CID 24817396
    .
  2. PMID 15013545
    .
  3. ^
    PMID 14585945
    .
  4. ^
    S2CID 6771526
    .
  5. PMID 15383472
    .
  6. ^
    S2CID 3665578
    .
  7. PMID 22276081
    .
  8. ^
    PMID 16148288
    .
  9. ^
    PMID 22503439
    .
  10. ^
    PMID 21241354
    .
  11. PMID 8145785
    . WOS:A1994NJ51200008.
  12. ^
    PMID 8087958
    .
  13. ISBN 978-0-19-956908-3. {{cite book}}: |first= has generic name (help)CS1 maint: multiple names: authors list (link
    )
  14. ^
    PMID 12356489
    .
  15. ^
    PMID 18449411
    .
  16. ^
    PMID 21457505
    .
  17. ^ "Lepirudin Injection". American Society of Health-System Pharmacists. Retrieved 18 September 2012.
  18. ^
    S2CID 25332427
    .
  19. ^
    PMID 15692265
    .
  20. ^ a b heartwire. "FDA opts not to approve ximelagatran". Retrieved 19 September 2012.
  21. PMID 11960487
    .
  22. PMID 22231617
    .
  23. ^ "Iprivask 15 mg" (PDF). Retrieved 18 September 2012.
  24. ^ "Angiomax Injection" (PDF). Food and Drug Administration. Retrieved 18 September 2012.
  25. ^ "FDA approves Pradaxa to prevent stroke in people with atrial fibrillation". Food and Drug Administration. Retrieved 18 September 2012.
  26. ^
    PMID 22742650
    .
  27. ^ "AZD0837". Astrazenecaclinicaltrials.com. Retrieved 2012-10-16.
  28. ^ AstraZeneca Long-term treatment with the oral direct thrombin inhibitor AZD0837, compared to Vitamin-K antagonists, as stroke prevention in patients with non-valvular atrial fibrillation and one or more risk factors for stroke and systemic embolic events. A 5-year follow-up study study code D1250C0004221 January 2010 Trial D1250C00042 Archived November 10, 2013, at the Wayback Machine
  29. PMID 20368532
    .
  30. PMID 19690349
    .
Retrieved from "https://en.wikipedia.org/w/index.php?title=Discovery_and_development_of_direct_thrombin_inhibitors&oldid=1189884985"