Development of MDL 28,050, a Small Stable Antithrombin Agent Based on a Functional Domain of the Leech Protein, Hirudin

Krstenansky, John L.; Broersma, Robert J.; Owen, Thomas J.; Payne, Marguerite H.; Yates, Mark T.; Mao, Simon J.T.

doi:10.1055/s-0038-1645196

Cited by 58 publications

(36 citation statements)

References 12 publications

(24 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Furthermore, a series of bivalent thrombin inhibitors termed hirunorms was generated that contain a peptidic module that blocks the active-site in a nonsubstrate mode [82,83]. Other variations of the initially developed hirulogs include modifications in the linker [84,85] and the fibrinogen exosite-binding region [86,87] as well as size reduction of the hirudin-derived part, as in BCH-2763 [88]. More recently, a chimera of hirudin and dipetalogastin II, a potent peptidic thrombin inhibitor from the bug Dipetalogaster maximus was described which exhibited an inhibition equilibrium constant (K i ) of 45 fM [89] which is close to that of natural hirudin.…”

Section: Early Direct Thrombin Inhibitorsmentioning

confidence: 99%

Direct thrombin inhibitors – a survey of recent developments

Schwienhorst¹

2006

Cell. Mol. Life Sci.

View full text Add to dashboard Cite

Thrombin is a plasma serine protease that plays a key role in coagulation and hemostasis but also in thromboembolic diseases. Direct thrombin inhibitors could, therefore, be beneficial for future anticoagulant therapy in the prophylaxis of venous and arterial thrombosis as well as myocardial infarction. However, development of direct thrombin inhibitors has brought researchers more heartache than success. The most recent setback came this year when AstraZeneca withdrew Ximelagatran, the first orally bioavailable direct thrombin inhibitor that had received regulatory approval (France, 2003), after reports of serious hepatoxicity in a fraction of patients. This review describes the status of direct thrombin inhibitors, focusing on drug candidates that are at present in clinical trials. In addition, some more recent research strategies in the design of novel direct thrombin inhibitors are discussed, which may very well contribute to future developments of potent anticoagulants.

show abstract

Section: Early Direct Thrombin Inhibitorsmentioning

confidence: 99%

Direct thrombin inhibitors – a survey of recent developments

Schwienhorst¹

2006

Cell. Mol. Life Sci.

View full text Add to dashboard Cite

show abstract

“…The hirudin analog displayed as high an anticoagulant potency in vitro (CTT2 = 3.2 f 0.4 p~, concentration of peptide that doubles thrombin time) and duration of action in vivo (increase of prothrombin time by a factor Fm = 2.03 f 0.15 after 15 min at the dose of 8 mg/kg, rat, i.v.) as one of the most potent reference compounds, succinyl-Tyr-Glu-Pro-Ile-Pro-Glu-Glu-Ala-Cha-~-Glu-OH (MDL 28050, Cha = cyclohexyl-t-alanine) [8], for which the values under the same conditions were CTT2 = 2.4 f 0.4 p~ and Fm = 2.14 f 0.15.…”

Section: I] (Scheme 2)mentioning

confidence: 99%

“…The corresponding position is occupied by tyrosine 04-sulfate in natural hirudin [8]. The usual conditions used for cleavage of the peptide from the resin left intact the protecting groups on the phosphono and OH group of tyrosine.…”

Section: I] (Scheme 2)mentioning

confidence: 99%

See 1 more Smart Citation

Enantioselective Synthesis of (2S)‐2‐Amino‐3‐(4‐hydroxy‐3‐phosphonophenyl)propionic Acid (= 3′‐Phosphono‐L‐tyrosine) and Its Incorporation into Peptides

Paladino¹,

Guyard²,

Thurieau³

et al. 1993

Helvetica Chimica Acta

View full text Add to dashboard Cite

The asymmetric synthesis of derivatives of the new amino acid (2S)-2-amino-3-(4-hydroxy-3-phosphonopheny1)propionic acid (3'-phosphono-~-tyrosine; ,]) is described. The protected amino acid 13 is obtained oia a Schdlkopfsynthesis by coupling of the rearranged orrho-phosphonophenolic side chain (see Scheme I, 6a) with the lithiated bis-lactim ether 8 of cyclo(-o-valyl-glycyl-) (see Scheme 2). The incorporation of the protected amino acid 14 in a biologically active dodecapeptide is successfully achieved by the [(9H-fluoren-9-yl)-methoxylcarbonyl (Fmoc) strategy of solid-phase peptide synthesis. Differential protection of ,] provides four levels of selective deprotection of, in the order, the N2-amino, the carboxyl (cleavage from the resin), the phenol, and the phosphono function (+peptide 16).Introduction. -Phosphorylation of tyrosine residues in proteins plays an important role in signal-transduction pathways during cell transformation and hormone-induced cell growth [I] [2]. Together protein tyrosine kinases and phosphatases catalyze the reversible transfer of phosphate to tyrosyl residues of enzymes and other proteins. Peptides containing analogs of phosphotyrosine may serve either as product inhibitors of kinases or as substrate inhibitors of phosphatases and, therefore, have potential as anticancer drugs. Both as a building block during peptide synthesis and as a constitutive residue in the final peptide, phosphotyrosine suffers from being easily hydrolyzable under acidic conditions [3], and several attempts were made to stabilize the attachment of the phosphate group on the aryl moiety, including the replacement of the phenolic 0-atom by a CH, or CF, group [4-61, or the replacement of the aryl C-0 bond by a C-P bond [7]. However, these methods either introduce an additional methylene group between the aromatic ring and the phosphate group or eliminate the phenolic function of tyrosine. We report here on the enantioselective preparation of a new phosphono derivative of tyrosine in which the free phenolic function is maintained in position 4' and the phosphono group attached to the aromatic ring in position 3' by a stable C-P bond. We describe several protected derivatives suitable for peptide synthesis and the incorporation of one deriva-

show abstract

“…Further chemical optimization of this sequence gave more potent and stable analogs such as MDL 28050, a W-succinylated, non-sulfonated peptide with nonnatural amino-acid substitutions [8]. The importance of sulfonation [9] [ 101 or phosphorylation [ 111 of ~-tyrosine-63 was also investigated and found to consistently increase the anticoagulant activity.…”

mentioning

confidence: 99%

Synthesis of a New Bivalent Hirudin Analog (hirufos), which includes a stable 4′‐phosphono‐L‐phenylalanine mimic of (L‐tyrosine O⁴‐sulfate)‐63

Thurieau

Guyard

Simonet

et al. 1994

Helvetica Chimica Acta

View full text Add to dashboard Cite

The synthesis on solid phase of a new derivative of the anticoagulant protein hirudin is described (see Scheme and Fig. I , I). The henicosapeptide is a bivalent conjugate of the C-terminus of hirudin and of the active-site-binding tetrapeptide D-Phe-Pro-Arg-Pro linked via a tetraglycine spacer. The peptide, for which the name hirufos was coined, incorporates a stable phosphono derivative of L-phenylalanine which, combined with the other structural modifications, leads to a potent anticoagulant agent. Synthesis was readily achieved by the (9H-fluoren-9-yl)-methoxycarbonyl (Fmoc) strategy followed by acidolytic cleavage from the resin and deprotection, including the liberation of the crucial phosphonic group on L-phenylalanine.Introduction. -Hirudin is a 0-sulfonated peptide of 65 amino acids firstly isolated from the salivary glands of the blood-sucking leech Hirudo medicinalis [I] and endowed with strong anticoagulant properties. The polypeptide binds tightly to the fibrinogenrecognizing site of a-thrombin, thus leading to an efficient inhibition of the protease [2]. X-Ray data analysis of the cocrystal convincingly demonstrated an interaction between the carboxy-terminal tail of hirudin (residues 48 to 65) and a long groove on the surface of the enzyme [3]. In addition, hirudin binds with its N-terminal part (Val-Val-Tyr) to the thrombin active sit cleft. The therapeutic potential of hirudin was soon realized, and the peptide (desulfohirudin) is currently produced on large scale by biotechnological means [4], and a number of advantages of recombinant hirudin over heparins are reported [5].

show abstract

Development of MDL 28,050, a Small Stable Antithrombin Agent Based on a Functional Domain of the Leech Protein, Hirudin

Cited by 58 publications

References 12 publications

Direct thrombin inhibitors – a survey of recent developments

Direct thrombin inhibitors – a survey of recent developments

Enantioselective Synthesis of (2S)‐2‐Amino‐3‐(4‐hydroxy‐3‐phosphonophenyl)propionic Acid (= 3′‐Phosphono‐L‐tyrosine) and Its Incorporation into Peptides

Synthesis of a New Bivalent Hirudin Analog (hirufos), which includes a stable 4′‐phosphono‐L‐phenylalanine mimic of (L‐tyrosine O⁴‐sulfate)‐63

Contact Info

Product

Resources

About

Development of MDL 28,050, a Small Stable Antithrombin Agent Based on a Functional Domain of the Leech Protein, Hirudin

Cited by 58 publications

References 12 publications

Direct thrombin inhibitors – a survey of recent developments

Direct thrombin inhibitors – a survey of recent developments

Enantioselective Synthesis of (2S)‐2‐Amino‐3‐(4‐hydroxy‐3‐phosphonophenyl)propionic Acid (= 3′‐Phosphono‐L‐tyrosine) and Its Incorporation into Peptides

Synthesis of a New Bivalent Hirudin Analog (hirufos), which includes a stable 4′‐phosphono‐L‐phenylalanine mimic of (L‐tyrosine O4‐sulfate)‐63

Contact Info

Product

Resources

About

Synthesis of a New Bivalent Hirudin Analog (hirufos), which includes a stable 4′‐phosphono‐L‐phenylalanine mimic of (L‐tyrosine O⁴‐sulfate)‐63