Development of 2-aryl substituted quinazolin-4(3H)-one,pyrido[4,3-d]pyrimidin-4(3H)-one and pyrido[2,3-d]pyrimidin-4(3H)-one derivatives as microsomal prostaglandin E2 synthase-1 inhibitors |
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| Affiliation: | 1. Department of Chemistry, Faculty of Sciences, University of Guilan, P.O. Box 41335-1914, Rasht, Iran;2. Department of Chemistry, Islamic Azad University, Rasht Branch, Iran;1. Division of Drug Discovery Research, Korea Research Institute of Chemical Technology, Yuseong-gu, Daejeon 305-343, Republic of Korea;2. Department of Medicinal and Pharmaceutical Chemistry, University of Science and Technology, Yuseong-gu, Daejeon 305-350, Republic of Korea;1. Boehringer Ingelheim Pharma GmbH & Co. KG, Department of Medicinal Chemistry, Birkendorfer Str. 65, 88397 Biberach an der Riss, Germany;2. Boehringer Ingelheim Pharma GmbH & Co. KG, Department of Cardiometabolic Research, Birkendorfer Str. 65, 88397 Biberach an der Riss, Germany;3. Boehringer Ingelheim Pharma GmbH & Co. KG, Department of Drug Discovery Support Research Germany, Birkendorfer Str. 65, 88397 Biberach an der Riss, Germany;1. Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, PO Box 2457, Riyadh 11451, Saudi Arabia;2. Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, PO Box 35516, Mansoura, Egypt;3. Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, PO Box 35516, Mansoura, Egypt;4. Department of Pharmacology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia;5. Department of Pharmaceutics and Pharmaceutical Technology (Microbiology), College of Pharmacy, Taibah University, Almadinah Almunawwarah 344, Saudi Arabia |
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| Abstract: | mPGES-1 is inducible terminal synthase acting downstream of COX enzymes in arachidonic acid pathway, regulates the biosynthesis of pro-inflammatory prostaglandin PGE2. Cardiovascular side effect of coxibs and NSAIDs, selective for COX-2 inhibition, stimulated interest in mPGES-1, a therapeutic target with potential to deliver safe and effective anti-inflammatory drugs. The synthesis and structure activity relationship of a series of compounds from 2-aryl substituted quinazolin-4(3H)-one, pyrido[4,3-d]pyrimidin-4(3H)-one and pyrido[2,3-d]pyrimidin-4(3H)-one scaffolds as mPGES-1 inhibitor are discussed. A set of analogs (28, 48, 49) were identified with <10 nM potencies in the recombinant human mPGES-1 enzyme and in the A549 cellular assays. These analogs were also found to be potent in the human whole blood assay (<400 nM). Furthermore, the representative compound 48 was shown to be selective with other prostanoid synthases and was able to effectively regulate PGE2 biosynthesis in clinically relevant inflammatory settings, in comparison with celecoxib. |
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| Keywords: | Analgesic Cyclooxygenase mPGES-1 Quinazolinone |
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