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Oxyfunctionalization of Pharmaceuticals by Fungal Peroxygenases
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Jan Kiebist, Martin Hofrichter, Ralf Zuhse, Katrin Scheibner
The enzymatic synthesis of the human metabolites of the bile acid reabsorption inhibitor volixibat (72) by MroUPO is an exemplary reaction of practical relevance (Fig. 18.20). This drug candidate was incipiently developed by Sanofi (SAR548304) and is currently under clinic investigation in phase I by Shire (SHP626) for the treatment of adults suffering from non-alcoholic steatohepatitis (NASH) (Siebers et al., 2018). Stepwise N-demethylation was the main metabolic pathway observed in internal Sanofi in vitro studies with human and hamster microsomes (containing P450s). Identical products were obtained when incubating volixibat with MroUPO (Kiebist et al., 2015). Furthermore, both mono- (73) and bis-N-demethylation metabolites (74) could be prepared in one-pot conversions via two kinetically controlled approaches yielding 49% and 66%. In contrast, the chemical synthesis required five steps starting from a volixibat precursor to obtain an overall yield of 74 of 27%. Gradual N-demethylation of volixibat (72) catalyzed by MroUPO in two different kinetically controlled approaches. [a] The first metabolite was isolated after 90 min. [b] In a second approach, 74 was isolated after complete reaction.
Present and emerging pharmacotherapies for non-alcoholic steatohepatitis in adults
Published in Expert Opinion on Pharmacotherapy, 2019
Yuji Ogawa, Masato Yoneda, Takashi Kobayashi, Yasushi Honda, Takaomi Kessoku, Kento Imajo, Satoru Saito, Atsushi Nakajima
Volixibat (SHP626; formerly LUM002) is a highly potent, minimally absorbed, competitive inhibitor of the apical sodium-dependent bile acid transporter (ASBT) [84]. Volixibat inhibits the reabsorption of bile acids in the ileum, thereby reducing the amount of bile acids in enterohepatic circulation. As a result, volixibat is thought to reduce the amount of free cholesterol in the liver by inducing the synthesis of new bile acids from cholesterol. Free cholesterol is highly hepatotoxic and is considered as a factor that can exacerbate NASH [85].
Safety considerations for the management of cholestatic itch
Published in Expert Opinion on Drug Safety, 2021
The ileal bile acid transporter is a brush border glycoprotein expressed on the luminal side of the distal ileum and is responsible for the reabsorption of bile acids that are then recirculated to the liver via portal venous flow completing the enterohepatic circulation cycle [22]. Since expression of these receptors is upregulated in cholestatic disorders, a newer class of agents that block this critical step - IBAT inhibitors - are currently in different stages of development, some of them showing promising results. For instance, linerixibat (GSK2330672) is an IBAT inhibitor that demonstrated efficacy for the management of pruritus in initial smaller clinical trials [23] and most recently in a randomized, double-blind, phase 2b study (GLIMMER) that lasted 12 weeks and randomized 147 patients with PBC. Although 31–78% of patients in the study-drug arms experienced adverse events, with the most common symptoms being diarrhea and abdominal pain, drug discontinuation rate was acceptable (10%) [24]. Better education about the management of diarrhea while on IBAT inhibitors will likely improve tolerability. A phase 3, open-label study, aiming to evaluate the long-term safety of linerixibat is currently recruiting patients (NCT04167358) and a phase 3 randomized, placebo controlled-trial is planned to start soon. Maralixibat (LUM001, SHP-625) has shown a similar safety profile in clinical trials [25] and is currently being evaluated for the management of pediatric cholestatic disorders (NCT03905330, NCT04524390). Volixibat is currently under evaluation in a phase II trial for the treatment of pruritus in patients with PSC (NCT04663308). Notably, patients with PSC and inflammatory bowel disease who have undergone total colectomy with ileal pouch anal anastomosis have been excluded from clinical trials with IBAT inhibitors so far and it is unclear whether they would benefit from this class of drugs.