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3. On the Failure Initiation in the Proximal Human Femur Under Simulated Sideways Fall.

Author

Bahaloo, Hassan, Enns-Bray, W. S., Fleps, I., Ariza, O., Gilchrist, S., Soyka, R. Widmer, Guy, P., Palsson, H., Ferguson, S. J., Cripton, P. A., and Helgason, B.

Abstract

The limitations of areal bone mineral density measurements for identifying at-risk individuals have led to the development of alternative screening methods for hip fracture risk including the use of geometrical measurements from the proximal femur and subject specific finite element analysis (FEA) for predicting femoral strength, based on quantitative CT data (qCT). However, these methods need more development to gain widespread clinical applications. This study had three aims: To investigate whether proximal femur geometrical parameters correlate with obtained femur peak force during the impact testing; to examine whether or not failure of the proximal femur initiates in the cancellous (trabecular) bone; and finally, to examine whether or not surface fracture initiates in the places where holes perforate the cortex of the proximal femur. We found that cortical thickness around the trochanteric-fossa is significantly correlated to the peak force obtained from simulated sideways falling ( R = 0.69) more so than femoral neck cortical thickness ( R = 0.15). Dynamic macro level FE simulations predicted that fracture generally initiates in the cancellous bone compartments. Moreover, our micro level FEA results indicated that surface holes may be involved in primary failure events. [ABSTRACT FROM AUTHOR]

Published
2018
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9. Guanidine Derivatives as Combined Thromboxane A<INF>2</INF> Receptor Antagonists and Synthase Inhibitors

Author

Soyka, R., Guth, B. D., Weisenberger, H. M., Luger, P., and Muller, T. H.

Abstract

A new series of ω-disubstituted alkenoic acid derivatives derived from samixogrel 5 were designed and synthesized as combined thromboxane A2 receptor antagonists/thromboxane A2 synthase inhibitors with improved solubility and reduced protein binding compared to 5. Hexenoic acid derivatives with a 3-pyridyl group and 3-(2-cyano-3-alkyl-guanidino)phenyl substituent were found to be optimal with regard to this dual mode of action. The most potent compound, E-6-(3-(2-cyano-3-tert-butyl-guanidino)phenyl)-6-(3-pyridyl)hex-5-enoic acid, “terbogrel” 32 inhibits the thromboxane A2 synthase in human gel-filtered platelets with an IC50 value of 4.0 ± 0.5 nM (n = 4). Radioligand binding studies with 3H-SQ 29,548 revealed that 32 blocks the thromboxane A2/endoperoxide receptor on washed human platelets with an IC50 of 11 ± 6 nM (n = 2) and with an IC50 of 38 ± 1 nM (n = 15) in platelet-rich plasma. Terbogrel inhibits the collagen-induced platelet aggregation in human platelet-rich plasma and whole blood with an IC50 of 310 ± 18 nM (n = 8) and 52 ± 20 nM (n = 6), respectively. This was shown to translate into a potent antithrombotic effect in vivo as demonstrated in studies using a model of arterial thrombosis in rabbits (ED50 = 0.19 ± 0.07 mg/kg; n = 20). Thus, terbogrel is the first compound with a guanidino moiety demonstrating both a potent TXA2 synthase inhibition and a potent TXA2 receptor antagonism and has been selected for further clinical development.

Published
1999

13. Poster session Wednesday 11 December all day display: 11/12/2013, 09:30-16:00 * Location: Poster area

Author

Bertrand, PB, Grieten, L, Smeets, C, Verbrugge, FH, Mullens, W, Vrolix, M, Rivero-Ayerza, M, Verhaert, D, Vandervoort, P, Tong, L, Ramalli, A, Tortoli, P, Dhoge, J, Bajraktari, G, Lindqvist, P, Henein, MY, Obremska, M, Boratynska, MB, Kurcz, JK, Zysko, DZ, Baran, TB, Klinger, MK, Darahim, K, Mueller, H, Carballo, D, Popova, N, Vallee, J-P, Floria, M, Chistol, R, Tinica, G, Grecu, M, Rodriguez Serrano, M, Osa-Saez, A, Rueda-Soriano, J, Buendia-Fuentes, F, Domingo-Valero, D, Igual-Munoz, B, Alonso-Fernandez, P, Quesada-Carmona, A, Miro-Palau, V, Palencia-Perez, M, Bech-Hanssen, O, Polte, CL, Lagerstrand, K, Janulewicz, M, Gao, S, Erdogan, E, Akkaya, M, Bacaksiz, A, Tasal, A, Sonmez, O, Turfan, M, Kul, S, Vatankulu, MA, Uyarel, H, Goktekin, O, Mincu, RI, Magda, LS, Mihaila, S, Florescu, M, Mihalcea, D, Enescu, OE, Chiru, A, Popescu, B, Tiu, C, Vinereanu, D, 112/2011, Research grant, Broch, K, Kunszt, G, Massey, R, De Marchi, SF, Aakhus, S, Gullestad, L, Urheim, S, Yuan, L, Feng, JL, Jin, XY, Bombardini, T, Casartelli, M, Simon, D, Gaspari, MG, Procaccio, F, Hasselberg, NE, Haugaa, KH, Brunet, A, Kongsgaard, E, Donal, E, Edvardsen, T, Sahin, TAYLAN, Yurdakul, S, Cengiz, BETUL, Bozkurt, AYSEN, Aytekin, SAIDE, Cesana, F, Spano, F, Santambrogio, G, Alloni, M, Vallerio, P, Salvetti, M, Carerj, S, Gaibazzi, N, Rigo, F, Moreo, A, Group, APRES Collaborative, Wdowiak-Okrojek, K, Michalski, B, Kasprzak, JD, Shim, A, Lipiec, P, Generati, G, Pellegrino, M, Bandera, F, Donghi, V, Alfonzetti, E, Guazzi, M, Marcun, R, Stankovic, I, Farkas, J, Vlahovic-Stipac, A, Putnikovic, B, Kadivec, S, Kosnik, M, Neskovic, AN, Lainscak, M, Iliuta, L, Szymanski, P, Lipczynska, M, Klisiewicz, A, Sobieszczanska-Malek, M, Zielinski, T, Hoffman, P, Gjerdalen, G F, Hisdal, J, Solberg, EE, Andersen, TE, Radunovic, Z, Steine, K, Svanadze, A, Poteshkina, N, Krylova, N, Mogutova, P, Shim, A, Kasprzak, JD, Szymczyk, E, Wdowiak-Okrojek, K, Michalski, B, Stefanczyk, L, Lipiec, P, Benedek, T, Matei, C, Jako, B, Suciu, ZS, Benedek, I, Yaroshchuk, N A, Kochmasheva, V V, Dityatev, V P, Kerbikov, O B, Przewlocka-Kosmala, M, Orda, A, Karolko, B, Mysiak, A, Kosmala, W, Rechcinski, T, Wierzbowska-Drabik, K, Lipiec, P, Chmiela, M, Kasprzak, JD, Aziz, A, Hooper, J, Rayasamudra, S, Uppal, H, Asghar, O, Potluri, R, Zaroui, A, Mourali, MS, Rezine, Z, Mbarki, S, Jemaa, M, Aloui, H, Mechmeche, R, Farhati, A, Gripari, P, Maffessanti, F, Tamborini, G, Muratori, M, Fusini, L, Vignati, C, Bartorelli, AL, Alamanni, F, Agostoni, PG, Pepi, M, Ruiz Ortiz, M, Mesa, D, Delgado, M, Seoane, T, Carrasco, F, Martin, M, Mazuelos, F, Suarez De Lezo Herreros De Tejada, J, Romero, M, Suarez De Lezo, J, Brili, S, Stamatopoulos, I, Misailidou, M, Chrisochoou, C, Christoforatou, E, Stefanadis, C, Ruiz Ortiz, M, Mesa, D, Delgado, M, Martin, M, Seoane, T, Carrasco, F, Ojeda, S, Segura, J, Pan, M, Suarez De Lezo, J, Cammalleri, V, Ussia, GP, Muscoli, S, Marchei, M, Sergi, D, Mazzotta, E, Romeo, F, Igual Munoz, B, Bel Minguez, ABM, Perez Guillen, MPG, Maceira Gonzalez, AMG, Monmeneu Menadas, JVMM, Hernandez Acuna, CHA, Estornell Erill, JEE, Lopez Lereu, PLL, Francisco Jose Valera Martinez, FJVM, Montero Argudo, AMA, Sunbul, M, Akhundova, A, Sari, I, Erdogan, O, Mutlu, B, Cacicedo, A, Velasco Del Castillo, S, Anton Ladislao, A, Aguirre Larracoechea, U, Rodriguez Sanchez, I, Subinas Elorriaga, A, Oria Gonzalez, G, Onaindia Gandarias, J, Laraudogoitia Zaldumbide, E, Lekuona Goya, I, Ding, W, Zhao, Y, Lindqvist, P, Nilson, J, Winter, R, Holmgren, A, Ruck, A, Henein, MY, Attenhofer Jost, C H, Soyka, R, Oxenius, A, Kretschmar, O, Valsangiacomo Buechel, ER, Greutmann, M, Weber, R, Keramida, K, Kouris, N, Kostopoulos, V, Karidas, V, Damaskos, D, Makavos, G, Paraskevopoulos, K, Olympios, CD, Eskesen, K, Olsen, NT, Fritz-Hansen, T, Sogaard, P, Cameli, M, Lisi, M, Righini, FM, Curci, V, Massoni, A, Natali, B, Maccherini, M, Chiavarelli, M, Massetti, M, Mondillo, S, Mabrouk Salem Omar, A, Ahmed Abdel-Rahman, M, Khorshid, H, Rifaie, O, Santoro, C, Santoro, A, Ippolito, R, De Palma, D, De Stefano, F, Muscariiello, R, Galderisi, M, Squeri, A, Censi, S, Baldelli, M, Grattoni, C, Cremonesi, A, Bosi, S, Saura Espin, D, Gonzalez Canovas, C, Gonzalez Carrillo, J, Oliva Sandoval, MJ, Caballero Jimenez, L, Espinosa Garcia, MD, Garcia Navarro, M, Valdes Chavarri, M, De La Morena Valenzuela, G, Ryu, SK, Shin, DG, Son, JW, Choi, JH, Goh, CW, Choi, JW, Park, JY, Hong, GR, Sklyanna, O, Yuan, L, Yuan, L, Planinc, I, Bagadur, G, Ljubas, J, Baricevic, Z, Skoric, B, Velagic, V, Bijnens, B, Milicic, D, Cikes, M, Gospodinova, M, Chamova, T, Guergueltcheva, V, Ivanova, R, Tournev, I, Denchev, S, Ancona, R, Comenale Pinto, S, Caso, P, Arenga, F, Coppola, MG, Calabro, R, Neametalla, H, Boitard, S, Hamdi, H, Planat-Benard, V, Casteilla, L, Li, Z, Hagege, AA, Mericskay, M, Menasche, P, Agbulut, O, Merlo, M, Stolfo, D, Anzini, M, Negri, F, Pinamonti, B, Barbati, G, Di Lenarda, A, Sinagra, G, Stolfo, D, Merlo, M, Pinamonti, B, Gigli, M, Poli, S, Porto, A, Di Nora, C, Barbati, G, Di Lenarda, A, Sinagra, G, Coppola, C, Piscopo, G, Cipresso, C, Rea, D, Maurea, C, Esposito, E, Arra, C, Maurea, N, Nemes, A, Kalapos, A, Domsik, P, Forster, T, Voilliot, D, Huttin, O, Vaugrenard, T, Schwartz, J, Sellal, J-M, Aliot, E, Juilliere, Y, Selton-Suty, C, Sanchez Millan, P J, Cabeza Lainez, P, Castillo Ortiz, J, Chueca Gonzalez, EM, Gheorghe, L, Fernandez Garcia, P, Herruzo Rojas, MS, Del Pozo Contreras, R, Fernandez Garcia, M, Vazquez Garcia, R, Rosca, M, Popescu, BA, Botezatu, D, Calin, A, Beladan, CC, Gurzun, M, Enache, R, Ginghina, C, Farouk, H, Al-Maimoony, T, Alhadad, A, El Serafi, M, Abdel Ghany, M, Poorzand, H, Mirfeizi, SZ, Javanbakht, A, center, Preventive Cardiovascular care research, center, Lupus Research, sciences, Mashhad university of medical, Tellatin, S, Famoso, G, Dassie, F, Martini, C, Osto, E, Maffei, P, Iliceto, S, Tona, F, Radunovic, Z, Steine, KS, Jedrzejewska, I, Braksator, W, Krol, W, Swiatowiec, A, Sawicki, J, Kostarska-Srokosz, E, Dluzniewski, M, Maceira Gonzalez, A M, Cosin-Sales, J, Diago, JL, Aguilar, J, Ruvira, J, Monmeneu, J, Igual, B, Lopez-Lereu, MP, Estornell, J, Olszanecka, A, Dragan, A, Kawecka-Jaszcz, K, Czarnecka, D, Scholz, F, Gaudron, PD, Hu, K, Liu, D, Florescu, C, Herrmann, S, Bijnens, B, Ertl, G, Stoerk, S, Weidemann, F, Krestjyaninov, M, Razin, VA, Gimaev, RH, Bogdanovic, Z, Burazor, I, Deljanin Ilic, M, Peluso, D, Muraru, D, Cucchini, U, Mihaila, S, Casablanca, S, Pigatto, E, Cozzi, F, Punzi, L, Badano, LP, Iliceto, S, Zhdanova, E, Rameev, VV, Safarova, AF, Moisseyev, SV, Kobalava, ZD, Magnino, C, Omede, P, Avenatti, E, Presutti, D, Losano, I, Moretti, C, Bucca, C, Gaita, F, Veglio, F, Milan, A, Bellsham-Revell, H, Bell, AJ, Miller, OI, Simpson, JM, Hwang, YM, Kim, GH, Jung, MH, Woo, GH, Medicine, Department of Internal, Hospital, St.Vincents, Korea, The Catholic University of, Suwon, Division of Cardiology, Repu, Driessen, MMP, Leiner, T, Schoof, PH, Breur, JMPJ, Sieswerda, GT, Meijboom, FJ, Bellsham-Revell, H, Hayes, N, Anderson, D, Austin, BC, Razavi, R, Greil, GF, Simpson, JM, Bell, AJ, Zhao, XX, Xu, XD, Qin, YW, Szmigielski, C A, Styczynski, G, Sobczynska, M, Placha, G, Kuch-Wocial, A, Ikonomidis, I, Voumbourakis, A, Triantafyllidi, H, Pavlidis, G, Varoudi, M, Papadakis, I, Trivilou, P, Paraskevaidis, I, Anastasiou-Nana, M, Lekakis, I, Kong, WILL, Yip, JAMES, Ling, LH, Milan, A, Tosello, F, Leone, D, Bruno, G, Losano, I, Avenatti, E, Sabia, L, Veglio, F, Zaborska, B, Baran, J, Pilichowska-Paszkiet, E, Sikora-Frac, M, Michalowska, I, Kulakowski, P, Budaj, A, Mega, S, Bono, MC, De Francesco, V, Castiglione, I, Ranocchi, F, Casacalenda, A, Goffredo, C, Patti, G, Di Sciascio, G, Musumeci, F, Kennedy, M, Waterhouse, DF, Sheahan, R, Foley, DF, Mcadam, BF, Ancona, R, Comenale Pinto, S, Caso, P, Arenga, F, Coppola, MG, Calabro, R, Remme, E W, Smedsrud, M K, Hasselberg, N E, Smiseth, O A, Edvardsen, T, Halmai, L, Nemes, A, Kardos, A, Neubauer, S, Degiovanni, A, Baduena, L, Dellera, G, Occhetta, E, Marino, P, Hotchi, J, Yamada, H, Nishio, S, Bando, M, Hayashi, S, Hirata, Y, Amano, R, Soeki, T, Wakatsuki, T, Sata, M, Lamia, B, Molano, LC, Viacroze, C, Cuvelier, A, Muir, JF, Lipczynska, M, Piotr Szymanski, PS, Anna Klisiewicz, AK, Lukasz Mazurkiewicz, LM, Piotr Hoffman, PH, Van T Sant, J, Wijers, SC, Ter Horst, IAH, Leenders, GE, Cramer, MJ, Doevendans, PA, Meine, M, Hatam, N, Goetzenich, A, Aljalloud, A, Mischke, K, Hoffmann, R, Autschbach, R, Sikora-Frac, M, Zaborska, B, Maciejewski, P, Bednarz, B, Budaj, A, Evangelista, A, Torromeo, C, Pandian, NG, Nardinocchi, P, Varano, V, Schiariti, M, Teresi, L, Puddu, PE, Storve, S, Dalen, H, Snare, SR, Haugen, BO, Torp, H, Fehri, W, Mahfoudhi, H, Mezni, F, Annabi, MS, Taamallah, K, Dahmani, R, Haggui, A, Hajlaoui, N, Lahidheb, D, Haouala, H, Colombo, A, Carminati, MC, Maffessanti, F, Gripari, P, Pepi, M, Lang, RM, Caiani, EG, Walker, JR, Abadi, S, Agmon, Y, Carasso, S, Aronson, D, Mutlak, D, Lessick, J, Saxena, A, Ramakrishnan, S, Juneja, R, Ljubas, J, Reskovic Luksic, V, Matasic, R, Pezo Nikolic, B, Lovric, D, Separovic Hanzevacki, J, Quattrone, A, Zito, C, Alongi, G, Vizzari, G, Bitto, A, De Caridi, G, Greco, M, Tripodi, R, Pizzino, G, Carerj, S, Ibrahimi, P, Jashari, F, Johansson, E, Gronlund, C, Bajraktari, G, Wester, P, Henein, MY, Kosmala, W, Marwick, TH, Souza, J R M, Zacharias, L G T, Geloneze, B, Pareja, J C, Chaim, A, Nadruz, W JR, Coelho, O R, Apostolovic, S, Stanojevic, D, Jankovic-Tomasevic, R, Salinger-Martinovic, S, Djordjevic-Radojkovic, D, Pavlovic, M, Tahirovic, E, Musial-Bright, L, Lainscak, M, Duengen, HD, group, CIBIS ELD study, Filipiak, D, Kasprzak, JD, and Lipiec, P

Abstract

Purpose: With the advent of percutaneous transcatheter device closures in congenital heart defects and the emergence of percutaneous left atrial appendage closure, there is an increasingly important role for echocardiographic guidance and control of device position and function. Disc occluder devices frequently present as an unexplained ‘figure-of-8’ on echocardiography. The aim of this study was to clarify this ‘figure-of-8’ display and to relate its morphology to transducer position and device type. Methods: A mathematical model was developed to resemble disc occluder geometry and to allow a numerical simulation of the echocardiographic appearance. In addition, we developed an in vitro set-up for echocardiographic analysis of various disc occluders and various transducer positions. Results: In the mathematical model of an epitrochoid curve (closely resembling disc occluder geometry) a ‘figure-of-8’ display is obtained when emphasizing points with tangent vector perpendicular to the direction of ultrasound waves. Decreasing imaging depth results in a more asymmetric ‘figure-of-8’, with small upper part and wide lower part. Clinical and in vitro data are in close agreement with these results (Figure 1). Furthermore a ‘figure-of-8’ display is only obtained in a coronal imaging position, and is similar for different commercially available disc occluder types. Conclusions: The ‘figure-of-8’ display in the ultrasound image of a disc occluder is an imaging artifact due to the specific ‘epitrochoidal’ geometry of a deployed device and its interaction with ultrasound waves. The morphology of the ‘figure-of-8’ depends on transducer position, i.e. imaging depth, and is similar for different device types. Figure 1 Impact of imaging depth

Published
2013
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16. Morphology based anisotropic finite element models of the proximal femur validated with experimental data.

Author

Enns-Bray WS, Ariza O, Gilchrist S, Widmer Soyka RP, Vogt PJ, Palsson H, Boyd SK, Guy P, Cripton PA, Ferguson SJ, and Helgason B

Subjects
Aged, Aged, 80 and over, Anisotropy, Elastic Modulus, Female, Humans, Male, Stress, Mechanical, Tomography, X-Ray Computed, Femur diagnostic imaging, Finite Element Analysis
Abstract

Finite element analysis (FEA) of bones scanned with Quantitative Computed Tomography (QCT) can improve early detection of osteoporosis. The accuracy of these models partially depends on the assigned material properties, but anisotropy of the trabecular bone cannot be fully captured due to insufficient resolution of QCT. The inclusion of anisotropy measured from high resolution peripheral QCT (HR-pQCT) could potentially improve QCT-based FEA of the femur, although no improvements have yet been demonstrated in previous experimental studies. This study analyzed the effects of adding anisotropy to clinical resolution femur models by constructing six sets of FE models (two isotropic and four anisotropic) for each specimen from a set of sixteen femurs that were experimentally tested in sideways fall loading with a strain gauge on the superior femoral neck. Two different modulus-density relationships were tested, both with and without anisotropy derived from mean intercept length analysis of HR-pQCT scans. Comparing iso- and anisotropic models to the experimental data resulted in nearly identical correlation and highly similar linear regressions for both whole bone stiffness and strain gauge measurements. Anisotropic models contained consistently greater principal compressive strains, approximately 14% in magnitude, in certain internal elements located in the femoral neck, greater trochanter, and femoral head. In summary, anisotropy had minimal impact on macroscopic measurements, but did alter internal strain behavior. This suggests that organ level QCT-based FE models measuring femoral stiffness have little to gain from the addition of anisotropy, but studies considering failure of internal structures should consider including anisotropy to their models., (Copyright © 2016 IPEM. Published by Elsevier Ltd. All rights reserved.)

Published
2016
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17. Facile entry to an efficient and practical enantioselective synthesis of a polycyclic cholesteryl ester transfer protein inhibitor.

Author

Han ZS, Xu Y, Fandrick DR, Rodriguez S, Li Z, Qu B, Gonnella NC, Sanyal S, Reeves JT, Ma S, Grinberg N, Haddad N, Krishnamurthy D, Song JJ, Yee NK, Pfrengle W, Ostermeier M, Schnaubelt J, Leuter Z, Steigmiller S, Däubler J, Stehle E, Neumann L, Trieselmann T, Tielmann P, Buba A, Hamm R, Koch G, Renner S, Dehli JR, Schmelcher F, Stange C, Mack J, Soyka R, and Senanayake CH

Subjects
Crystallography, X-Ray, Hydrogenation, Molecular Conformation, Molecular Structure, Pyridines chemistry, Stereoisomerism, Cholesterol Ester Transfer Proteins antagonists & inhibitors, Pyridines chemical synthesis, Pyridines pharmacology
Abstract

An efficient enantioselective synthesis of the chiral polycyclic cholesteryl ester transfer protein (CETP) inhibitor 1 has been developed. The synthesis was rendered practical for large scale via the development of a modified Hantzsch-type reaction to prepare the sterically hindered pyridine ring, enantioselective hydrogenation of hindered ketone 6 utilizing novel BIBOP-amino-pyridine derived Ru complex, efficient ICl promoted lactone formation, and a BF3 mediated hydrogenation process for diastereoselective lactol reduction. This efficient route was successfully scaled to produce multikilogram quantities of challenging CETP drug candidate 1.

Published
2014
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19. Pulmonary pharmacology of DT-TX 30 SE, a potent selective combined thromboxane synthetase inhibitor and receptor antagonist, in guinea pigs.

Author

Meade CJ, Muacevic G, Ward P, and Soyka R

Subjects
15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid, Animals, Arachidonic Acid pharmacology, Bronchial Spasm chemically induced, Bronchial Spasm drug therapy, Dinoprostone biosynthesis, Enzyme Inhibitors pharmacology, Guinea Pigs, Male, Prostaglandin Endoperoxides, Synthetic pharmacology, Thromboxane A2 analogs & derivatives, Thromboxane A2 pharmacology, Thromboxane B2 biosynthesis, Fatty Acids, Unsaturated pharmacology, Lung drug effects, Lung physiology, Pyridines pharmacology, Receptors, Thromboxane antagonists & inhibitors, Thromboxane-A Synthase antagonists & inhibitors
Abstract

A novel chemical compound, DT-TX 30 SE (E-6-(4-2-(4-chlorobenzenesulphonylamino)-ethyl)phenyl)-6-(3-pyrid yl)- hex-5-enoic acid), was studied in various models of guinea pig pulmonary function. The compound was a potent inhibitor (ED50 0.019 mg/kg, i.v.) of bronchospasm induced by the thromboxane receptor agonist U-46619, indicating thromboxane receptor antagonism. At even lower doses (ED50 0.0036 mg/kg, i.v.), it blocked arachidonic acid-induced bronchospasm. Interpretation of the latter results as evidence for additional thromboxane synthetase inhibitory activity was supported by the inhibition of arachidonic acid- or bradykinin-induced thromboxane B2 production in an isolated lung preparation, although prostaglandin E2 and prostaglandin 6-oxo-F(1 alpha) production measured at the same time were not inhibited. The potency of DT-TX 30 SE was compared with thromboxane receptor antagonists and synthetase inhibitors described in the literature. As a receptor antagonist, DT-TX 30 SE was significantly more potent than BM 13505 and BM 13177 (assessed by antagonism of U-46619-induced bronchospasm), but less potent than SQ 29548, while as a thromboxane synthetase inhibitor, it was significantly more potent than OKY 046 and UK 37248 as assessed by antagonism of arachidonic acid-induced bronchospasm or (OKY 046) inhibition of thromboxane production in isolated lung. The compound was active by the oral route as shown by its ability, at 10 mg/kg, p.o., to significantly reduce the immediate allergic response of sensitized guinea pigs to an ovalbumin aerosol.

Published
1996
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20. 6,6-Disubstituted Hex-5-enoic acid derivatives as combined thromboxane A2 receptor antagonists and synthetase inhibitors.

Author

Soyka R, Heckel A, Nickl J, Eisert W, Müller TH, and Weisenberger H

Subjects
Blood Platelets metabolism, Bridged Bicyclo Compounds, Heterocyclic, Collagen pharmacology, Drug Design, Humans, Hydrazines metabolism, Molecular Conformation, Molecular Structure, Phosphodiesterase Inhibitors pharmacology, Platelet Aggregation drug effects, Platelet Aggregation Inhibitors pharmacology, Receptors, Thromboxane metabolism, Structure-Activity Relationship, Thromboxane A2 chemistry, Thromboxane-A Synthase blood, Tritium, Fatty Acids, Unsaturated chemical synthesis, Fatty Acids, Unsaturated pharmacology, Pyridines chemical synthesis, Pyridines pharmacology, Receptors, Thromboxane antagonists & inhibitors, Thromboxane-A Synthase antagonists & inhibitors
Abstract

A series of omega-disubstituted alkenoic acid derivatives were designed and synthesized as antithrombotic inhibitors of thromboxane A2 synthetase and thromboxane A2 receptor antagonists. Hexenoic acid derivatives with a 3-pyridyl group and a 4-(2-benzenesulfonamidoethyl)phenyl substituent were found to be optimal with regard to the dual mode of action. The most potent compound, (E)-6-(4-(2-(((4-chlorophenyl)sulfonyl)amino)ethyl)phenyl)-6-(3-pyridyl) hex-5-enoic acid (36), inhibits thromboxane A2 synthetase in gel-filtered human platelets with an IC50 value of 4.5 +/- 0.5 nM (n = 4), whereas an inhibitory effect on cyclooxygenase is seen only at a much higher concentration (IC50: 240 microM). Radioligand-binding studies with [3H]SQ 29,548 in washed human platelets revealed that 36 blocks the prostaglandin H2/thromboxane A2 receptor with an IC50 of 19 +/- 5 nM (n = 5) and is therefore 85-fold more potent than another combined thromboxane A2 synthetase inhibitor/receptor antagonist, Ridogrel (4). Compound 36 inhibits the collagen-induced platelet aggregation in human platelet-rich plasma and whole blood with an EC50 of 1 microM (Ridogrel: 16 microM) and 100 nM, respectively, and was selected for further development.

Published
1994
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