Subsequent to the formation of PGH₂, the cytochrome P450 activities thromboxane synthase (CYP5A1, TBXAS1, P24557 , EC 5.3.99.5) and prostacyclin synthase (CYP8A1, PTGIS, Q16647, EC 5.3.99.4) generate thromboxane A₂ and prostacyclin (PGI₂), respectively. Additionally, multiple enzyme activities are able to generate prostaglandin E₂ (PGE₂), prostaglandin D₂ (PGD₂) and prostaglandin F_2α (PGF_2α). PGD₂ can be metabolised to 9α,11β-prostacyclin F_2α through the multifunctional enzyme activity of AKR1C3. PGE₂ can be metabolised to 9α,11β-prostaglandin F_2α through the 9-ketoreductase activity of CBR1. Conversion of the 15-hydroxyecosanoids, including prostaglandins, lipoxins and leukotrienes to their keto derivatives by the NAD-dependent enzyme HPGD leads to a reduction in their biological activity.

YS121 has been reported to inhibit mPGES1 and 5-LOX with a pIC₅₀ value of 5.5 [16].

* Key recommended reading is highlighted with an asterisk

* Liu Y, He S, Chen Y, Liu Y, Feng F, Liu W, Guo Q, Zhao L, Sun H. (2020) Overview of AKR1C3: Inhibitor Achievements and Disease Insights. J Med Chem, 63 (20): 11305-11329. [PMID:32463235]

1. Aritake K, Kado Y, Inoue T, Miyano M, Urade Y. (2006) Structural and functional characterization of HQL-79, an orally selective inhibitor of human hematopoietic prostaglandin D synthase. J Biol Chem, 281 (22): 15277-86. [PMID:16547010]

2. Chadli A, Bouhouche I, Sullivan W, Stensgard B, McMahon N, Catelli MG, Toft DO. (2000) Dimerization and N-terminal domain proximity underlie the function of the molecular chaperone heat shock protein 90. Proc Natl Acad Sci USA, 97 (23): 12524-9. [PMID:11050175]

3. Faull AW, Brewster AG, Brown GR, Smithers MJ, Jackson R. (1995) Dual-acting thromboxane receptor antagonist/synthase inhibitors: synthesis and biological properties of [2-substituted-4-(3-pyridyl)-1,3-dioxan-5-yl] alkenoic acids. J Med Chem, 38 (4): 686-94. [PMID:7861416]

4. Geng Y, Li W, Wong NK, Xue F, Li Q, Zhang Y, Xu J, Deng Z, Zhou Y. (2024) Discovery of Artemisinins as Microsomal Prostaglandins Synthase-2 Inhibitors for the Treatment of Colorectal Cancer via Chemoproteomics. J Med Chem, 67 (3): 2083-2094. [PMID:38287228]

5. Giroux A, Boulet L, Brideau C, Chau A, Claveau D, Côté B, Ethier D, Frenette R, Gagnon M, Guay J et al.. (2009) Discovery of disubstituted phenanthrene imidazoles as potent, selective and orally active mPGES-1 inhibitors. Bioorg Med Chem Lett, 19 (20): 5837-41. [PMID:19748780]

6. Gorman RR, Johnson RA, Spilman CH, Aiken JW. (1983) Inhibition of platelet thromboxane A2 synthase activity by sodium 5-(3'-pyridinylmethyl)benzofuran-2-carboxylate. Prostaglandins, 26 (2): 325-42. [PMID:6316421]

7. Gresele P, Deckmyn H, Arnout J, Nenci GG, Vermylen J. (1989) Characterization of N,N'-bis(3-picolyl)-4-methoxy-isophtalamide (picotamide) as a dual thromboxane synthase inhibitor/thromboxane A2 receptor antagonist in human platelets. Thromb Haemost, 61 (3): 479-84. [PMID:2552606]

8. Gryglewski RJ, Bunting S, Moncada S, Flower RJ, Vane JR. (1976) Arterial walls are protected against deposition of platelet thrombi by a substance (prostaglandin X) which they make from prostaglandin endoperoxides. Prostaglandins, 12 (5): 685-713. [PMID:824685]

9. Gryglewski RJ, Szczeklik A, Korbut R, Swies J, Musiał J, Krzanowski M, Maga P. (1995) The mechanism of anti-thrombotic, thrombolytic and fibrinolytic actions of camonagrel--a new thromboxane synthase inhibitor. Wien Klin Wochenschr, 107 (9): 283-9. [PMID:7778318]

10. Hatae T, Hara S, Yokoyama C, Yabuki T, Inoue H, Ullrich V, Tanabe T. (1996) Site-directed mutagenesis of human prostacyclin synthase: Alteration of Cys441 of the Cys-pocket, and Glu347 and Arg350 of the EXXR motif. FEBS Lett, 389 (3): 268-72. [PMID:8766713]

11. Hiraku S, Taniguchi K, Wakitani K, Omawari N, Kira H, Miyamoto T, Okegawa T, Kawasaki A, Ujiie A. (1986) Pharmacological studies on the TXA2 synthetase inhibitor (E)-3-[p-(1H-imidazol-1-ylmethyl)phenyl]-2-propenoic acid (OKY-046). Jpn J Pharmacol, 41 (3): 393-401. [PMID:3093741]

12. Irikura D, Aritake K, Nagata N, Maruyama T, Shimamoto S, Urade Y. (2009) Biochemical, functional, and pharmacological characterization of AT-56, an orally active and selective inhibitor of lipocalin-type prostaglandin D synthase. J Biol Chem, 284 (12): 7623-30. [PMID:19131342]

13. Jegerschöld C, Pawelzik SC, Purhonen P, Bhakat P, Gheorghe KR, Gyobu N, Mitsuoka K, Morgenstern R, Jakobsson PJ, Hebert H. (2008) Structural basis for induced formation of the inflammatory mediator prostaglandin E2. Proc Natl Acad Sci USA, 105 (32): 11110-5. [PMID:18682561]

14. Johnson J, Corbisier R, Stensgard B, Toft D. (1996) The involvement of p23, hsp90, and immunophilins in the assembly of progesterone receptor complexes. J Steroid Biochem Mol Biol, 56 (1-6 Spec No): 31-7. [PMID:8603045]

15. Kobayashi T, Nakatani Y, Tanioka T, Tsujimoto M, Nakajo S, Nakaya K, Murakami M, Kudo I. (2004) Regulation of cytosolic prostaglandin E synthase by phosphorylation. Biochem J, 381 (Pt 1): 59-69. [PMID:15040786]

16. Koeberle A, Zettl H, Greiner C, Wurglics M, Schubert-Zsilavecz M, Werz O. (2008) Pirinixic acid derivatives as novel dual inhibitors of microsomal prostaglandin E2 synthase-1 and 5-lipoxygenase. J Med Chem, 51 (24): 8068-76. [PMID:19053751]

17. Leclerc P, Idborg H, Spahiu L, Larsson C, Nekhotiaeva N, Wannberg J, Stenberg P, Korotkova M, Jakobsson PJ. (2013) Characterization of a human and murine mPGES-1 inhibitor and comparison to mPGES-1 genetic deletion in mouse models of inflammation. Prostaglandins Other Lipid Mediat, 107: 26-34. [PMID:24045148]

18. Maddox JF, Serhan CN. (1996) Lipoxin A4 and B4 are potent stimuli for human monocyte migration and adhesion: selective inactivation by dehydrogenation and reduction. J Exp Med, 183 (1): 137-46. [PMID:8551217]

19. Matsuura K, Shiraishi H, Hara A, Sato K, Deyashiki Y, Ninomiya M, Sakai S. (1998) Identification of a principal mRNA species for human 3alpha-hydroxysteroid dehydrogenase isoform (AKR1C3) that exhibits high prostaglandin D2 11-ketoreductase activity. J Biochem, 124 (5): 940-6. [PMID:9792917]

20. Nabe T, Kuriyama Y, Mizutani N, Shibayama S, Hiromoto A, Fujii M, Tanaka K, Kohno S. (2011) Inhibition of hematopoietic prostaglandin D synthase improves allergic nasal blockage in guinea pigs. Prostaglandins Other Lipid Mediat, 95 (1-4): 27-34. [PMID:21601002]

21. Qiu W, Zhou M, Mazumdar M, Azzi A, Ghanmi D, Luu-The V, Labrie F, Lin SX. (2007) Structure-based inhibitor design for an enzyme that binds different steroids: a potent inhibitor for human type 5 17beta-hydroxysteroid dehydrogenase. J Biol Chem, 282 (11): 8368-79. [PMID:17166832]

22. Randall MJ, Parry MJ, Hawkeswood E, Cross PE, Dickinson RP. (1981) UK-37, 248, a novel, selective thromboxane synthetase inhibitor with platelet anti-aggregatory and anti-thrombotic activity. Thromb Res, 23 (1-2): 145-62. [PMID:6795753]

23. Riendeau D, Aspiotis R, Ethier D, Gareau Y, Grimm EL, Guay J, Guiral S, Juteau H, Mancini JA, Méthot N et al.. (2005) Inhibitors of the inducible microsomal prostaglandin E2 synthase (mPGES-1) derived from MK-886. Bioorg Med Chem Lett, 15 (14): 3352-5. [PMID:15953724]

24. Shiro T, Kakiguchi K, Takahashi H, Nagata H, Tobe M. (2013) 7-Phenyl-imidazoquinolin-4(5H)-one derivatives as selective and orally available mPGES-1 inhibitors. Bioorg Med Chem, 21 (11): 2868-78. [PMID:23623673]

25. Skarydová L, Zivná L, Xiong G, Maser E, Wsól V. (2009) AKR1C3 as a potential target for the inhibitory effect of dietary flavonoids. Chem Biol Interact, 178 (1-3): 138-44. [PMID:19007764]

26. Takusagawa F. (2013) Microsomal prostaglandin E synthase type 2 (mPGES2) is a glutathione-dependent heme protein, and dithiothreitol dissociates the bound heme to produce active prostaglandin E2 synthase in vitro. J Biol Chem, 288 (14): 10166-10175. [PMID:23426368]

27. Watanabe K, Ohkubo H, Niwa H, Tanikawa N, Koda N, Ito S, Ohmiya Y. (2003) Essential 110Cys in active site of membrane-associated prostaglandin E synthase-2. Biochem Biophys Res Commun, 306 (2): 577-81. [PMID:12804604]

28. Wu Y, Karna S, Choi CH, Tong M, Tai HH, Na DH, Jang CH, Cho H. (2011) Synthesis and biological evaluation of novel thiazolidinedione analogues as 15-hydroxyprostaglandin dehydrogenase inhibitors. J Med Chem, 54 (14): 5260-4. [PMID:21650226]

29. Yamada T, Komoto J, Watanabe K, Ohmiya Y, Takusagawa F. (2005) Crystal structure and possible catalytic mechanism of microsomal prostaglandin E synthase type 2 (mPGES-2). J Mol Biol, 348 (5): 1163-76. [PMID:15854652]

30. Yamada T, Takusagawa F. (2007) PGH2 degradation pathway catalyzed by GSH-heme complex bound microsomal prostaglandin E2 synthase type 2: the first example of a dual-function enzyme. Biochemistry, 46 (28): 8414-24. [PMID:17585783]

31. Zimmermann TJ, Niesen FH, Pilka ES, Knapp S, Oppermann U, Maier ME. (2009) Discovery of a potent and selective inhibitor for human carbonyl reductase 1 from propionate scanning applied to the macrolide zearalenone. Bioorg Med Chem, 17 (2): 530-6. [PMID:19097799]

Angelo A. Izzo Department of Pharmacy School of Medicine and Surgery University of Naples Federico II Naples, Italy