Oxidative metabolism of razuprotafib (AKB-9778), a sulfamic acid phosphatase inhibitor, in human microsomes and recombinant human CYP2C8 enzyme

Abstract

1. Razuprotafib, a sulphamic acid-containing phosphatase inhibitor, is shown in vivo to undergo enzymatic oxidation and methylation to form a major metabolite in monkey and human excreta with an m/z^– value of 633.

2. LC-MS/MS analysis of samples derived from incubations of razuprotafib with human liver microsomes and recombinant CYP2C8 enzyme has elucidated the metabolic pathway for formation of the thiol precursor to the S-methyl metabolite MS633 (m/z^– 633).

3. Under in vitro conditions, the major pathway of razuprotafib metabolism involves extensive oxidation of the thiophene and phenyl rings.

4. A single oxidation takes place at one of the phenyl groups. Multiple oxidations occur at the thiophene moiety: initial oxidation results in the formation of a thiolactone followed by a second oxidation giving rise to an S-oxide of the thiolactone, which is further metabolised to the ring-opened form and ultimate formation of a thiol (m/z^– 619).

5. An additional mono-oxidation pathway involves epoxidation of the thiophene followed by hydrolysis to a diol.

6. The thiol and diol metabolites are trapped by the addition of a nucleophilic trapping agent, 3-methoxyphenacyl bromide (MPB), giving adducts with m/z^– 767.

7. The thiol is a likely precursor to the major in vivo razuprotafib metabolite, MS633.

Keywords:

• Razuprotafib
• AKB-9778
• VE-PTP
• sulphamic acid
• thiophene
• metabolism
• microsomes
• CYP2C8

Disclosure statement

No potential conflict of interest was reported by the author(s).