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In Vitro and in Vivo Pharmacological Characterization of BM-613, a Novel Dual Thromboxane Synthase Inhibitor and Thromboxane

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In Vitro and in Vivo Pharmacological Characterization of BM-613, a Novel Dual Thromboxane Synthase Inhibitor and Thromboxane JPET Fast Forward. Published on December 30, 2004 as DOI: 10.1124/jpet.104.079301 JPET FastThis Forward. article has not Published been copyedited on andDecember formatted. The 30, final 2004 version as mayDOI:10.1124/jpet.104.079301 differ from this version. JPET #79301 In vitro and in vivo pharmacological characterization of BM-613, a novel dual thromboxane synthase inhibitor and thromboxane receptor antagonist Julien Hanson*, Stephanie Rolin*, Denis Reynaud, Na Qiao, Leanne P. Kelley, Helen M. Reid, François Valentin, John Tippins, Therese B. Kinsella, Bernard Masereel, Cecil Pace- Downloaded from Asciak, Bernard Pirotte, and Jean-Michel Dogné Natural and Synthetic Drugs Research Centre, Department of Pharmacy, Laboratory of jpet.aspetjournals.org Medicinal Chemistry, University of Liège, 1, Av. de l'Hôpital, B-4000 Liège, Belgium. (J.H., J-M.D., B.P.) Department of Pharmacy, University of Namur, 61, rue de Bruxelles, B-5000 Namur, at ASPET Journals on September 24, 2021 Belgium. (S.R., B.M.) Programme in Integrative Biology, Research Institute, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8. (D.R., N.Q., C.P-A.) Department of Biochemistry, Conway Institute for Biomolecular and Biomedical Research, University College Dublin, Ireland. (L.P.K., H.M.R., T.B.K.) Department of Biological Sciences, Imperial College, Exhibition Road, London SW7 2AZ, United Kingdom. (F.V., J.T.) 1 Copyright 2004 by the American Society for Pharmacology and Experimental Therapeutics. JPET Fast Forward. Published on December 30, 2004 as DOI: 10.1124/jpet.104.079301 This article has not been copyedited and formatted. The final version may differ from this version. JPET #79301 a) Running title BM-613, an original antiplatelet and antithrombotic agent b) Corresponding author : Julien Hanson Natural and Synthetic Drugs Research Centre, Department of Pharmacy, Laboratory of Medicinal Chemistry, University of Liège, 1, Av de L'hôpital, 4000 Liège, Belgium. Phone : +3243664382 Downloaded from Fax : +3243664362 E-mail : [email protected] c) Number of text pages : 37 jpet.aspetjournals.org Number of Tables : 4 Number of Figures : 5 Number of References : 40 at ASPET Journals on September 24, 2021 Number of words in abstract : 249 Number of words in introduction : 674 Number of words in Discussion : 1493 List of nonstandard abbreviation : G-protein coupled receptor (GPCR), thromboxane receptor antagonist (TXRA), thromboxane synthase (TXS), thromboxane synthase inhibitor (TXSI), prostaglandin endoperoxide H2 (PGH2); e) Recommended section : cardiovascular 2 JPET Fast Forward. Published on December 30, 2004 as DOI: 10.1124/jpet.104.079301 This article has not been copyedited and formatted. The final version may differ from this version. JPET #79301 Abstract Thromboxane (TXA2) is a key mediator of platelet aggregation and smooth muscle contraction. Its action is mediated by its G-protein coupled receptor of which two isoforms, termed TPα and TPβ, occur in humans. TXA2 has been implicated in pathologies such as cardiovascular diseases, pulmonary embolism, atherosclerosis and asthma. This study describes the pharmacological characterization of BM-613, a new combined TXA2 receptor antagonist and TXA2 synthase inhibitor. It exhibits a strong affinity for human platelet TP Downloaded from receptors (IC50: 1.4 nM), TPα and TPβ expressed in COS-7 cells (IC50: 2.06 nM and 3.1 nM, respectively) and TPs expressed in human coronary artery smooth muscle cells (IC50: 29 µM). BM-613 shows a weak ability to prevent contraction of isolated rat aorta (ED50: 1.52 µM) and jpet.aspetjournals.org guinea-pig trachea (ED50: 2.5 µM) induced by TXA2 agonist U-46619. Besides, BM-613 antagonizes TPα (IC50: 0.11 µM) and TPβ (IC50: 0.17 µM) calcium mobilization induced by at ASPET Journals on September 24, 2021 U-46619 and inhibits human platelet aggregation induced by U-46619 (ED50: 0.278 µM), arachidonic acid (ED50: 0.375 µM) and the second wave of ADP. BM-613 also dose- dependently prevents TXA2 production by human platelets (IC50: 0.15 µM). In a rat model of ferric chloride induced thrombosis, BM-613 significantly reduces weight of formed thrombus by 79%, 49% and 28% at 5, 2 and 1 mg/kg (i.v.), respectively. In conclusion, BM-613 is a dual and potent TP receptor antagonist and TXA2 synthase inhibitor characterized by a strong antiplatelet and antithrombotic potency. These results suggest that BM-613 could be a potential therapeutic drug for thrombotic disorders. 3 JPET Fast Forward. Published on December 30, 2004 as DOI: 10.1124/jpet.104.079301 This article has not been copyedited and formatted. The final version may differ from this version. JPET #79301 Introduction Thromboxane A2 (TXA2) is a key lipid mediator characterized by several implications in physiological homeostasis including platelet aggregation and vascular and bronchial smooth muscle constriction (Hamberg et al., 1975; Moncada and Vane, 1978). An overproduction of TXA2 has been associated with many pathological states such as myocardial infarction, thrombosis and thrombotic disorders, unstable angina, pulmonary embolism, shock, atherosclerosis, preeclampsia and asthma (Dogne et al., 2004a). Downloaded from TXA2 is a metabolite of arachidonic acid (AA), a 20-carbon essential fatty acid stored in membrane phospholipids. Free AA can be released mainly by phospholipase A2 (PLA2) upon stimulation. TXA2 is synthesized in two steps: first the action of cyclooxygenase (COX) on jpet.aspetjournals.org free AA leads to the formation of prostaglandin H2 (PGH2) which can be subsequently metabolized by thromboxane synthase (TXS) into TXA2. COX exists in two main isoforms, COX-1 and COX-2, which are encoded by two separate at ASPET Journals on September 24, 2021 genes. COX-1 is expressed constitutively in most tissues mediating “housekeeping” functions, whereas COX-2 expression is mainly induced at sites of inflammation by various stimuli (Dogne et al., 2004a). The second is also expressed in a constitutive manner in endothelium (Cheng et al., 2002). TXA2 synthesis mainly occurs in platelets where COX-1 and thromboxane synthase are highly expressed. TXA2 actions are mediated by its G protein coupled receptor (GPCR), referred to as the TP receptor (Coleman et al., 1994). In 1991, Hirata et al. reported that human TP receptor was coded by one gene (Hirata et al., 1991), and in 1994, Raychowdhury et al. highlighted the existence of an isoform generated by alternative splicing (Raychowdhury et al., 1994). The two isoforms, named TPα and TPβ, share the same first 328 amino acids but differ by the length of their carboxy-terminal tails (15 amino acids of the α isoform being replaced by 79 amino acids in the β isoform). 4 JPET Fast Forward. Published on December 30, 2004 as DOI: 10.1124/jpet.104.079301 This article has not been copyedited and formatted. The final version may differ from this version. JPET #79301 Given the wide implications of TXA2 in several pathologies, studies have been undertaken in order to find therapeutic agents able to counteract the negative effects of TXA2. Indeed, therapeutic strategies include blocking the synthesis of TXA2 by the inhibition of TXS, antagonizing its action at the receptor level, or both. Thus, several TP receptor antagonists (TXRA) such as sulotroban (Stegmeier et al., 1984), thromboxane synthase inhibitors (TXSI) such as furegrelate (Gorman et al., 1983) and drugs combining both properties such as ridogrel and terbogrel have been developed. Dual compounds proved to be more interesting in Downloaded from therapeutics and as promising antithrombotic agents (Dogne et al., 2004a). Besides, acetylsalicylic acid (ASA, aspirin) is a non-steroïdal anti-inflammatory drug exerting its effects by irreversibly acetylating the active site of COX. In platelets, the inhibition is jpet.aspetjournals.org effective throughout the platelet life-time because they lack a nucleus. Since TXA2 is mainly produced by platelets, low-dose ASA has become the most common antiplatelet therapy used for secondary prevention of cardiovascular disease. Nevertheless, ASA is far from being a at ASPET Journals on September 24, 2021 panacea since it has been associated with Reye's syndrome and allergic reaction (asthma) and almost one third of patients receiving low-dose ASA do not respond, demonstrating a link between platelet function and the persistence of TXA2 production (Patrono, 2003). These later developments have strengthened the interest for development of other antithrombotic drugs such as TXA2 modulators. Herein we report the in vitro and in vivo pharmacological profile of BM-613 (Fig. 1), a new TXA2 modulator synthesized in our laboratory. BM-613 is a chemical derivative of BM-573, another thromboxane modulator combining TXRA and TXSI activities that has been widely described in literature (Rolin et al., 2001; Dogne et al., 2004b; Ghuysen et al., 2004; Lambermont et al., 2004). BM-613 has been developed as a dual TXRA and TXSI characterized by high activity on platelets compared to smooth muscle. In this study, we present several in vitro tests performed to characterize BM-613 effects on TXS, platelets and 5 JPET Fast Forward. Published on December 30, 2004 as DOI: 10.1124/jpet.104.079301 This article has not been copyedited and formatted. The final version may differ from this version. JPET #79301 smooth muscle. We have also carried out specific binding and antagonism of [Ca2+]i mobilization tests to compare the affinity and activity of our two compounds on the distinct TP receptors isoforms. Finally, an in vivo test is presented to evaluate the potential of BM-613 as an antithrombotic drug. Downloaded from jpet.aspetjournals.org at ASPET Journals on September 24, 2021 6 JPET Fast Forward. Published on December 30, 2004 as DOI: 10.1124/jpet.104.079301 This article has not been copyedited and formatted. The final version may differ from this version. JPET #79301 Materials and Methods Materials BM-613 (N-n-pentyl-N'-[2-(4'-methylphenylamino)-5-nitrobenzenesulfonyl]urea) and BM- 573 (N-tert-butyl-N’-[2-(4'-methylphenylamino)-5-nitrobenzenesulfonyl]urea) were synthesized in our laboratory.
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