Selective mPGES-1 Inhibitor Ameliorated Adjuvant-Induced Arthritis in the Rat Model
Endogenous prostaglandin E2 (PGE2) plays an important role in maintaining the homeostasis conditions. However, the overexpression of PGE2 in response to various inflammatory stimulations is an important target of anti-inflammatory drugs. Both inducible COX-2 (cyclooxygenase-2) and mPGES-1 (microsoma...
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| Format: | Article |
| Language: | English |
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Wiley
2024-01-01
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| Series: | Journal of Chemistry |
| Online Access: | http://dx.doi.org/10.1155/2024/5531519 |
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| author | Min Ji Kim Hwi-Ho Lee Choi Kim Ja Yeon Lee Kyung-Sook Chung Kyung-Tae Lee Jae Yeol Lee |
| author_facet | Min Ji Kim Hwi-Ho Lee Choi Kim Ja Yeon Lee Kyung-Sook Chung Kyung-Tae Lee Jae Yeol Lee |
| author_sort | Min Ji Kim |
| collection | DOAJ |
| description | Endogenous prostaglandin E2 (PGE2) plays an important role in maintaining the homeostasis conditions. However, the overexpression of PGE2 in response to various inflammatory stimulations is an important target of anti-inflammatory drugs. Both inducible COX-2 (cyclooxygenase-2) and mPGES-1 (microsomal prostaglandin E2 synthase-1) enzymes are responsible for the inflammatory overexpressed PGE2 production. Among them, mPGES-1 is regarded as a more promising ideal target for anti-inflammatory drugs without the gastrointestinal and cardiovascular side effects. As our continuous research for the discovery of novel mPGES-1 inhibitors, we have characterized MPO-0144 as a selective mPGES-1 inhibitor with a selectivity index of >270 over COX-1 and >25 over COX-2, respectively. Herein, we evaluated the anti-inflammatory effect of MPO-0144 in an adjuvant-induced arthritis rat model. MPO-0144 attenuated the inflammatory responses without severe gastrointestinal side effects and organ toxicities. These overall data suggest a possibility that MPO-0144 downregulates PGE2 production by potent mPGES-1 and weak COX-2 inhibitory activities, thus attenuating the paw swelling in AIA (adjuvant-induced arthritis) rat models. MPO-0144 also exhibited favorable ADMET profiles. However, MPO-0144 did not show any inhibitory effects on human mPGES-1 enzyme at a high concentration. Therefore, MPO-0144 represents a valuable pharmacological tool for the study of regulation of inducible mPGES-1 in an inflammatory arthritis rat model. |
| format | Article |
| id | doaj-art-4a377208c193482d8c6e8d10b7595e6f |
| institution | Kabale University |
| issn | 2090-9071 |
| language | English |
| publishDate | 2024-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of Chemistry |
| spelling | doaj-art-4a377208c193482d8c6e8d10b7595e6f2025-02-03T05:57:03ZengWileyJournal of Chemistry2090-90712024-01-01202410.1155/2024/5531519Selective mPGES-1 Inhibitor Ameliorated Adjuvant-Induced Arthritis in the Rat ModelMin Ji Kim0Hwi-Ho Lee1Choi Kim2Ja Yeon Lee3Kyung-Sook Chung4Kyung-Tae Lee5Jae Yeol Lee6Research Institute for Basic Sciences and Department of ChemistryDepartment of Pharmaceutical BiochemistryResearch Institute for Basic Sciences and Department of ChemistryResearch Institute for Basic Sciences and Department of ChemistryDepartment of Pharmaceutical BiochemistryDepartment of Pharmaceutical BiochemistryResearch Institute for Basic Sciences and Department of ChemistryEndogenous prostaglandin E2 (PGE2) plays an important role in maintaining the homeostasis conditions. However, the overexpression of PGE2 in response to various inflammatory stimulations is an important target of anti-inflammatory drugs. Both inducible COX-2 (cyclooxygenase-2) and mPGES-1 (microsomal prostaglandin E2 synthase-1) enzymes are responsible for the inflammatory overexpressed PGE2 production. Among them, mPGES-1 is regarded as a more promising ideal target for anti-inflammatory drugs without the gastrointestinal and cardiovascular side effects. As our continuous research for the discovery of novel mPGES-1 inhibitors, we have characterized MPO-0144 as a selective mPGES-1 inhibitor with a selectivity index of >270 over COX-1 and >25 over COX-2, respectively. Herein, we evaluated the anti-inflammatory effect of MPO-0144 in an adjuvant-induced arthritis rat model. MPO-0144 attenuated the inflammatory responses without severe gastrointestinal side effects and organ toxicities. These overall data suggest a possibility that MPO-0144 downregulates PGE2 production by potent mPGES-1 and weak COX-2 inhibitory activities, thus attenuating the paw swelling in AIA (adjuvant-induced arthritis) rat models. MPO-0144 also exhibited favorable ADMET profiles. However, MPO-0144 did not show any inhibitory effects on human mPGES-1 enzyme at a high concentration. Therefore, MPO-0144 represents a valuable pharmacological tool for the study of regulation of inducible mPGES-1 in an inflammatory arthritis rat model.http://dx.doi.org/10.1155/2024/5531519 |
| spellingShingle | Min Ji Kim Hwi-Ho Lee Choi Kim Ja Yeon Lee Kyung-Sook Chung Kyung-Tae Lee Jae Yeol Lee Selective mPGES-1 Inhibitor Ameliorated Adjuvant-Induced Arthritis in the Rat Model Journal of Chemistry |
| title | Selective mPGES-1 Inhibitor Ameliorated Adjuvant-Induced Arthritis in the Rat Model |
| title_full | Selective mPGES-1 Inhibitor Ameliorated Adjuvant-Induced Arthritis in the Rat Model |
| title_fullStr | Selective mPGES-1 Inhibitor Ameliorated Adjuvant-Induced Arthritis in the Rat Model |
| title_full_unstemmed | Selective mPGES-1 Inhibitor Ameliorated Adjuvant-Induced Arthritis in the Rat Model |
| title_short | Selective mPGES-1 Inhibitor Ameliorated Adjuvant-Induced Arthritis in the Rat Model |
| title_sort | selective mpges 1 inhibitor ameliorated adjuvant induced arthritis in the rat model |
| url | http://dx.doi.org/10.1155/2024/5531519 |
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