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Rational Design of Benzylidenehydrazinyl-Substituted Thiazole Derivatives as Potent Inhibitors of Human Dihydroorotate Dehydrogenase with in Vivo Anti-arthritic Activity.

Li S, Luan G, Ren X, Song W, Xu L, Xu M, Zhu J, Dong D, Diao Y, Liu X, Zhu L, Wang R, Zhao Z, Xu Y, Li H - Sci Rep (2015)

Bottom Line: Based on the X-ray structure of hDHODH in complex with lead compound 7, a series of benzylidenehydrazinyl-substituted thiazole derivatives as potent inhibitors of hDHODH were designed and synthesized, of which 19 and 30 were the most potent with IC50 values in the double-digit nanomolar range.Moreover, compound 19 displayed significant anti-arthritic effects and favorable pharmacokinetic profiles in vivo.Further X-ray structure and SAR analyses revealed that the potencies of the designed inhibitors were partly attributable to additional water-mediated hydrogen bond networks formed by an unexpected buried water between hDHODH and the 2-(2-methylenehydrazinyl)thiazole scaffold.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Bioreactor Engineering, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.

ABSTRACT
Human dihydroorotate dehydrogenase (hDHODH) is an attractive therapeutic target for the treatment of rheumatoid arthritis, transplant rejection and other autoimmune diseases. Based on the X-ray structure of hDHODH in complex with lead compound 7, a series of benzylidenehydrazinyl-substituted thiazole derivatives as potent inhibitors of hDHODH were designed and synthesized, of which 19 and 30 were the most potent with IC50 values in the double-digit nanomolar range. Moreover, compound 19 displayed significant anti-arthritic effects and favorable pharmacokinetic profiles in vivo. Further X-ray structure and SAR analyses revealed that the potencies of the designed inhibitors were partly attributable to additional water-mediated hydrogen bond networks formed by an unexpected buried water between hDHODH and the 2-(2-methylenehydrazinyl)thiazole scaffold. This work not only elucidates promising scaffolds targeting hDHODH for the treatment of rheumatoid arthritis, but also demonstrates that the water-mediated hydrogen bond interaction is an important factor in molecular design and optimization.

No MeSH data available.


Related in: MedlinePlus

Selected structures of reported hDHODH inhibitors.Compound 7 is the lead in this study identified in our previous work.
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f1: Selected structures of reported hDHODH inhibitors.Compound 7 is the lead in this study identified in our previous work.

Mentions: Clardy et al. first solved the three-dimensional crystal structures of hDHODH in complex with A771726 (1), the active metabolite of leflunomide (2), and a brequinar analog, providing the first insights into the specific structural features of class 2 DHODH enzymes. hDHODH is composed of two domains connected by an extended loop: a large α/β barrel C-terminal domain and a small N-terminal domain containing two α-helices7. The C-terminal domain offers binding sites for FMN and DHO, while the N-terminal domain houses the ubiquinone-binding site8. Several anti-tumor and immunosuppressive molecules have been reported to target hDHODH at the ubiquinone-binding site191011. The two best-studied examples (Fig. 1) are brequinar (3)12 and leflunomide (2)131415. The latter, which is the prodrug of the active metabolite A771726 (1), has been approved by the FDA for the treatment of rheumatoid arthritis. Unfortunately, both compounds are associated with various side effects. Brequinar was used for the treatment of cancer and graft-versus-host disease on the basis of satisfactory efficacy in animal models but failed in clinical trials due to its narrow therapeutic window16. Leflunomide has a disadvantageously long half-life of approximately two weeks in patients and has many side effects, such as symptomatic liver damage and interstitial lung disease17. Consequently, the identification of novel potent inhibitors of hDHODH as therapeutic agents that inhibit pyrimidine biosynthesis for the treatment of cancer and autoimmune diseases remains of considerable interest19.


Rational Design of Benzylidenehydrazinyl-Substituted Thiazole Derivatives as Potent Inhibitors of Human Dihydroorotate Dehydrogenase with in Vivo Anti-arthritic Activity.

Li S, Luan G, Ren X, Song W, Xu L, Xu M, Zhu J, Dong D, Diao Y, Liu X, Zhu L, Wang R, Zhao Z, Xu Y, Li H - Sci Rep (2015)

Selected structures of reported hDHODH inhibitors.Compound 7 is the lead in this study identified in our previous work.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4595849&req=5

f1: Selected structures of reported hDHODH inhibitors.Compound 7 is the lead in this study identified in our previous work.
Mentions: Clardy et al. first solved the three-dimensional crystal structures of hDHODH in complex with A771726 (1), the active metabolite of leflunomide (2), and a brequinar analog, providing the first insights into the specific structural features of class 2 DHODH enzymes. hDHODH is composed of two domains connected by an extended loop: a large α/β barrel C-terminal domain and a small N-terminal domain containing two α-helices7. The C-terminal domain offers binding sites for FMN and DHO, while the N-terminal domain houses the ubiquinone-binding site8. Several anti-tumor and immunosuppressive molecules have been reported to target hDHODH at the ubiquinone-binding site191011. The two best-studied examples (Fig. 1) are brequinar (3)12 and leflunomide (2)131415. The latter, which is the prodrug of the active metabolite A771726 (1), has been approved by the FDA for the treatment of rheumatoid arthritis. Unfortunately, both compounds are associated with various side effects. Brequinar was used for the treatment of cancer and graft-versus-host disease on the basis of satisfactory efficacy in animal models but failed in clinical trials due to its narrow therapeutic window16. Leflunomide has a disadvantageously long half-life of approximately two weeks in patients and has many side effects, such as symptomatic liver damage and interstitial lung disease17. Consequently, the identification of novel potent inhibitors of hDHODH as therapeutic agents that inhibit pyrimidine biosynthesis for the treatment of cancer and autoimmune diseases remains of considerable interest19.

Bottom Line: Based on the X-ray structure of hDHODH in complex with lead compound 7, a series of benzylidenehydrazinyl-substituted thiazole derivatives as potent inhibitors of hDHODH were designed and synthesized, of which 19 and 30 were the most potent with IC50 values in the double-digit nanomolar range.Moreover, compound 19 displayed significant anti-arthritic effects and favorable pharmacokinetic profiles in vivo.Further X-ray structure and SAR analyses revealed that the potencies of the designed inhibitors were partly attributable to additional water-mediated hydrogen bond networks formed by an unexpected buried water between hDHODH and the 2-(2-methylenehydrazinyl)thiazole scaffold.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Bioreactor Engineering, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.

ABSTRACT
Human dihydroorotate dehydrogenase (hDHODH) is an attractive therapeutic target for the treatment of rheumatoid arthritis, transplant rejection and other autoimmune diseases. Based on the X-ray structure of hDHODH in complex with lead compound 7, a series of benzylidenehydrazinyl-substituted thiazole derivatives as potent inhibitors of hDHODH were designed and synthesized, of which 19 and 30 were the most potent with IC50 values in the double-digit nanomolar range. Moreover, compound 19 displayed significant anti-arthritic effects and favorable pharmacokinetic profiles in vivo. Further X-ray structure and SAR analyses revealed that the potencies of the designed inhibitors were partly attributable to additional water-mediated hydrogen bond networks formed by an unexpected buried water between hDHODH and the 2-(2-methylenehydrazinyl)thiazole scaffold. This work not only elucidates promising scaffolds targeting hDHODH for the treatment of rheumatoid arthritis, but also demonstrates that the water-mediated hydrogen bond interaction is an important factor in molecular design and optimization.

No MeSH data available.


Related in: MedlinePlus