Wednesday, January 27, 2016

Topiroxostat I Xanthine Oxidase Inhibitor I Treatment for Gout | Treatment for Hyperuricemia

Topiroxostat [4-[5-(4-Pyridinyl)-1H-1,2,4-triazol-3-yl]-2-pyridinecarbonitrile] is an oral, non-purine, selective xanthine oxidase (XO) inhibitor developed for the treatment of gout and hyperuricemia. In medicinal terminology, Topiroxostat is an antihyperuricemic agent that reduces serum uric acid level by selectively inhibiting XOR and thereby suppressing uric acid production [1].

Topiroxostat: 2D and 3D Structure

Xanthine Oxidoreductase in Uric Acid Production:

Mammalian xanthine oxidoreductase (XOR) catalyzes the last two steps in the purine degradation pathway before formation of uric acid, i.e., hydroxylation of hypoxanthine to xanthine and xanthine to uric acid. The enzyme is a homodimer with molecular mass of 290 kDa; each subunit contains one molybdenum cofactor, two [2Fe-2S] centers, and one FAD center.

The oxidative hydroxylation of purine substrates takes place at the molybdenum center, and reducing equivalents thus introduced are transferred via the two [2Fe-2S] centers to the FAD center, where reduction of the physiological electron acceptor, NAD or O2, occurs.

Mammalian xanthine oxidoreductase (XOR) is a good target of drugs to treat gout and hyperuricemia. Allopurinol [4-hydroxypyrazolo(3,4-d)pyrimidine], a hypoxanthine isomer, was introduced as an inhibitor of XOR more than 40 years ago and has been extensively prescribed for gout and hyperuricemia patients.
Researchers have been trying to build new XOR inhibitors; and one of the success story is Febuxostat [2-(3-Cyano-4-isobutoxy-phenyl)-4-methyl-1,3-thiazole-5 carboxylic acid], which is a nonpurine selective inhibitor of XOR, and showed a more potent and longer-lasting urate-lowering effect than allopurinol in rodents. It was subsequently launched in US and EU for the treatment of gout.
Topiroxostat is developed as an unique type of XOR inhibitor. It not only forms a covalent linkage to molybdenum via oxygen in the hydroxylation reaction intermediate, but also interacts with amino acid residues of the solvent channel. For this unique exhibition of both structure- and mechanism-based inhibition, it is called termed as a hydrid-type inhibitor of XOR [1]. In addition, Topiroxostat has high bioavailability and safety in animals, hence it was short-listed as a candidate drug for hyperuricemia and gout.

Approval and Dosages:

Topiroxostat  (Tradename: Topiloric; Uriadec) was approved for use in Japan in June 2013. Fujiyakuhin Co., Ltd. and Sanwa Kagaku Kenkyusho Co., Ltd. are credited as the originators. The usual adult initial dosage is 20 mg/dose of topiroxostat orally administered twice daily in the morning and evening. Thereafter, the dose should be gradually increased, as needed, while monitoring blood uric acid levels. The usual maintenance dosage should be 60 mg/dose twice daily. The dose may be adjusted according to the patient’s condition, up to 80 mg/dose twice daily.

Topiroxostat Synthesis

WO2003064410A1: It is the oldest reported synthesis. It is considered expensive on account of TMSCN; and also N-protection/de-protection are considered as time and effort consuming.

Tetrahedron Lett 2008, 49(28), 4369-4371: It is considered as an improvement on Ref. 2. The starting material is commercially available and  Zn(CN)is much cheaper than TMSCN.

1H NMR (Estimated) for Topiroxostat

Experimental: 1H-NMR (DMSO-d6) δ ppm: 8.01 (2H, dd, J = 4.54 & 1.57 Hz), 8.31 (1H, dd, J = 5.11 & 1.65 Hz) , 8.53 (1H, dd, J = 1.65 & 0.50 Hz), 8.80 (2H, dd, J = 4.54 & 1.57 Hz), 8.93 (1H, dd, J = 5.11 & 0.50 Hz).

Sideeffects: The most come adverse reactions (AEs) reported are gout arthritis, cutaneous adverse events and hepatic impairment. These included gingival bleeding, oral pain, β2 microglobulin urine increase, NAG increase, blood amylase increase, eosinophilia, a1 microglobulin increase and platelet count increase. Liver disorder included ALT/AST increase, blood creatinine increase and high γ-GTP level. The patients also reported rash, cold sweat, urticaria and erythema. No bladder or kidney related AEs are reported.
1. Matsumoto, K.; et. al. FYX-051: a novel and potent hybrid-type inhibitor of xanthine oxidoreductase. J Pharmacol Exp Ther 2011, 336(1), 95-103.
2. Ashizawa, N.; et. al. Novel 1,2,4-triazole compound. WO2003064410A1
3. Huo, Z.; et. al. Zinc cyanide mediated direct a-cyanation of isonicotinic acid N-oxide. Application to the synthesis of FYX-051, a xanthine oxidoreductase inhibitor. Tetrahedron Lett 2008, 49(28), 4369-4371.
4. Sato, T.; et. al. Discovery of 3-(2-cyano-4-pyridyl)-5-(4-pyridyl)-1,2,4-triazole, FYX-051- a xanthine oxidoreductase inhibitor for the treatment of hyperuricemia. Bioorg Med Chem Lett 2009, 19(21), 6225-6229.
5. Approval for Topiroxostat (here).