Quantitation of an orally available thrombin inhibitor in rat, monkey and human plasma and in human urine by high-performance liquid chromatography and fluorescent post-column derivatization of arginine

Q2 · CHEMISTRY

Article

Author: M.M. Lods ; M.G. Ma ; C.B. Mendoza ; H.S. Tran ; R.F. Nutt ; K.T. Nguyen ; T.G. Nolan ; S.A. Dixon

An assay for the quantification of plasma and urine levels of CVS 1123, an orally bioavailable thrombin inhibitor, and its desmethyl form. CVS 738, was developed to support clinical and toxicology studies. This assay uses solid-phase extraction, reversed-phase HPLC separation, and post-column fluorescent derivatization with ninhydrin. An internal standard is added to correct for recovery. In aqueous solution, the arginine aldehyde structures of CVS 1123 and CVS 738 exist in multiple forms which can be separated under standard reversed-phase HPLC conditions. HPLC conditions were optimized to give rapid interconversion of the forms on the separation time scale, and consequently a single chromatographic peak. Extraction conditions were modified for quantitative extraction of drug compounds from large volumes of human plasma. The assay was shown to be accurate and precise, with a quantification limit of 17 ng CVS 1123/ml human plasma.

01 Feb 1997·Journal of Cardiovascular PharmacologyQ4 · MEDICINE

CVS-1123, A Direct Thrombin Inhibitor, Prevents Occlusive Arterial and Venous Thrombosis in a Canine Model of Vascular Injury

Q4 · MEDICINE

Article

Author: Lucchesi, Benedict R. ; Miller, Bernard V. ; Basler, Geoffrey C. ; Rebello, Sam S.

CVS-1123, low-molecular-weight, direct thrombin inhibitor was studied in an anesthetized canine model of arterial and venous thrombosis to determine whether thrombin inhibition could reduce the incidence of occlusive thrombosis in response to vessel-wall injury. The left carotid artery (LCA) and right jugular vein (RJV) were instrumented with a flow probe, intraluminal electrode, and critical stenosis. Either saline (n = 9), or CVS-1123 (n = 12) was administered in a loading dose of 2 mg/kg i.v., followed by an infusion (2.46 mg/kg/h for 180 min). Vessel-wall injury was initiated by applying a 300-microA anodal current to the intimal surface of the LCA and RJV. Platelet aggregation in response to gamma-thrombin remained inhibited by CVS-1123 for 8 h. The activated partial thromboplastin time (aPTT) was increased and remained elevated for the duration of the protocol. The prothrombin time (PT) showed an initial increase and then a rapid decrease after the infusion was discontinued. There was a twofold increase in the bleeding time (BT) at 2 h. The time to occlusion of the LCA was prolonged (380 +/- 22 min in the CVS-1123 group vs. 152 +/- 18 min in the saline group) with seven of 12 patent arteries at 8 h. Similarly, the time to occlusion for RJV was prolonged (415 +/- 16 min in the CVS-1123 group vs. 99 +/- 8 min in the saline group) with eight of 12 veins remaining patent at 8 h. CVS-1123 administration was associated with a decrease in the thrombus weights in both the LCA and RJV as compared with the saline-treated animals. In summary, CVS-1123 modifies the thrombogenic response to deep vessel-wall injury in both the arterial and venous circulations. The results suggest that CVS-1123 is an effective antithrombin and may offer a therapeutic alternative to current antithrombins in the management of arterial and venous thrombosis.

01 Oct 1996·CirculationQ1 · MEDICINE

Orally Effective CVS-1123 Prevents Coronary Artery Thrombosis in the Conscious Dog

Q1 · MEDICINE

Article

Author: Nolan, Thomas G. ; Rebello, Sam S. ; Friedrichs, Gregory S. ; Mendoza, Christine ; Cousins, Geoffrey R. ; Lucchesi, Benedict R. ; Rote, William E. ; Sudo, Yuji ; Vlasuk, George P.

Background We examined the oral efficacy of a direct thrombin inhibitor, CVS-1123 [(CH 3 CH 2 CH 2 ) 2 -CH-CO-Asp(OCH 3 )-Pro-Arg-CHO; MW, 575]. The object was to determine whether thrombin inhibition could reduce the incidence of occlusive coronary artery thrombosis in response to arterial wall injury. Methods and Results Arterial wall injury was induced in conscious dogs by a 150-μA anodal current applied to the intimal surface of the circumflex coronary artery 30 minutes after oral CVS-1123 (20 mg/kg every 8 hours for three doses; n=11) or placebo containing diluent (n=10). Dogs were monitored for 8 hours and at 24 hours. The coronary artery remained patent for 24 hours in 8 of 11 CVS-1123–treated dogs. All dogs (n=10) in the placebo group developed a sustained, occlusive arterial thrombus. Two hours after the initial oral dose, the plasma CVS-1123 concentration was 13±1 μg/mL, reaching a maximum of 15±1 μg/mL after the second dose and 4.4±0.5 μg/mL at 24 hours. Ex vivo platelet aggregation to γ-thrombin was inhibited and activated partial thromboplastin time was increased after treatment with CVS-1123 ( P <.05). Conclusions The direct thrombin inhibitor CVS-1123 is effective after oral administration in reducing the incidence of primary thrombus formation in an experimental model of arterial wall injury. Thrombin-specific inhibitors, such as CVS-1123, may be alternative antithrombotic agents in clinical settings in which heparin-associated thrombosis is a complicating factor or when long-term anticoagulation is required.

100 Deals associated with CVS-1123

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Indication	Highest Phase	Country/Location	Organization	Date
Angina, Unstable	Phase 1	US	Dendreon San Diego LLC	-
Angina, Unstable	Phase 1	GB	Schering-Plough Corp.	-
Angina, Unstable	Phase 1	-	Merck Sharp & Dohme Corp.	-
Coronary Artery Disease	Phase 1	-	Merck Sharp & Dohme Corp.	-
Coronary Thrombosis	Phase 1	GB	Schering-Plough Corp.	-
Coronary Thrombosis	Phase 1	US	Dendreon San Diego LLC	-
Venous Thromboembolism	Phase 1	-	Merck Sharp & Dohme Corp.	-
Venous Thrombosis	Phase 1	GB	Schering-Plough Corp.	-
Venous Thrombosis	Phase 1	US	Dendreon San Diego LLC	-

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