Inhibition of prostaglandin biosynthesis by SQ 28,852, A 7-oxabicyclo-[2.2.1]heptane analog |
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| Authors: | Don N Harris Marie B Phillips Inge M Michel Harold J Goldenberg Thomas E Steinbacher Martin L Ogletree Steven E Hall |
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| Institution: | 1. State Key Laboratory for Bioactive Substances and Functions of Natural Medicines, Nanwei Road A2, Beijing 100050, PR China;2. Beijing key laboratory of new drug mechanisms and pharmacological evaluation study, Nanwei Road A2, Beijing 100050, PR China;3. Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanwei Road A2, Beijing 100050, PR China;4. Institute of Food Science and Technology CAAS, Chinese Academy of Agricultural Sciences, No. 1 Nongda South Rd., Beijing 100193, PR China;1. Department of Clinical Pharmacy, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, Jiangsu, PR China;2. Department of Biopharmaceutics, School of Life Science and Technology, China Pharmaceutical University, Nanjing 211198, Jiangsu, PR China;3. Department of Geriatric Cardiology, Chinese PLA general hospital, Beijing100853, PR China;4. Department of Pharmacy, Nanjing University of Chinese Medicine Hanlin College, Taizhou 225300, Jiangsu, PR China;1. Department of Pharmacology and Therapeutics, University of Manitoba, Canada;2. Department of Pharmacology, College of Basic Medical Sciences, School of Nursing, Jilin University, Changchun 130021, China;3. Biochemistry and Medical Genetics, Center for Research and Treatment of Atherosclerosis, University of Manitoba, DREAM Children''s Hospital Research Institute of Manitoba, Winnipeg, Manitoba R3E 0T6, Canada;1. Center for Bioelectronics, Biosensors and Biochips (C3B), Department of Biomedical Engineering, Texas A&M University, College Station, TX 77843, USA;2. Department of Biomedical Engineering, Texas A&M University, College Station, TX 77843, USA;3. ABTECH Scientific, Inc., Biotechnology Research Park, 800 East Leigh Street, Richmond, VA 23219, USA |
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| Abstract: | 7-Oxabicyclo2.2.1]heptane analogs of prostaglandin (PG) H2 can act as thromboxane (Tx) A2 receptor antagonists or agonists, PGI2 and/rr PGD2 receptor agonists, or exhibit a mixture of the above activities. SQ 28,852, a new analog with a hexyloxymethyl omega side chain, is a potent inhibitor of PG synthesis. SQ 28,852 inhibited collagen and arachidonic acid (AA)-induced platelet aggregation and TxB2 and PGE2 formation, but did not block platelet aggregation induced by ADP or the TxA2 mimics, 9,11-azoPGH2, SQ 26,655, and U-46,619. It also blocked conversion of AA to TxB2, PGE2, and 6-ketoPGF1α by microsomal preparations of human platelets, bovine seminal vesicles, and bovine aortas, respectively, but did not inhibit the conversion of PGH2 to TxA2 by the platelet microsomal preparation. SQ 28,852 (p.o.) protected mice against the lethal effects of AA (75 mg/kg, i.v.). The I50 values for SQ 28,852, indomethacin and aspirin were 0.025, 0.05 and 15 mg/kg, respectively. Neither SQ 28.852 nor indomethacin protected mice from death caused by 9,11-azoPGH2. SQ 28,852 (0.01 to 1 mg/kg, i.v.) inhibited AA-induced bronchoconstriction in anesthetized guinea pigs for at least 60 min. As an inhibitor of AA-induced bronchoconstriction, SQ 28,852 was 16- and 45-times more potent than indomethacin at 3 and 60 min after i.v. administration, respectively. SQ 28,852 did not inhibit brochoconstriction induced by histamine or 9.11-azoPGH2, indicating its specificity of action
. SQ 28,852 is the first example of a new class of cyclooxygenase inhibitors whose structure is similar to that of the naturally occurring endoperoxide, PGH2. |
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