Polyhydroxylated Bile Acids for Cholestasis Treatment
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Solution Overview
Problem
Current treatments for biliary disorders, particularly those related to cholestasis and portal hypertension, are inadequate, as existing therapies fail to effectively stimulate bile flow and manage liver function in conditions like progressive familial intrahepatic cholestasis type 2 (PFIC2) and other cholestatic diseases.
Innovation Solution
The development of polyhydroxylated bile acids, such as tetrahydroxylated and pentahydroxylated bile acids, which are administered to stimulate bile flow and treat biliary disorders by targeting the MDR1 transporter, offering a choleretic effect and potential therapeutic benefit for conditions where BSEP function is impaired.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If traditional bile acids are used to treat biliary disorders, then bile flow stimulation is achieved, but toxicity increases
Solution Approach 1:
The patent applies parameter changes by modifying the chemical structure of bile acids to create polyhydroxylated derivatives with at least four hydroxyl groups. This structural modification changes the physicochemical parameters of the bile acid, resulting in compounds that are more effective at stimulating bile flow while simultaneously reducing toxicity compared to traditional bile acids.
2Productivity
If BSEP is targeted for bile acid secretion, then bile flow is maintained, but in PFIC2 patients with BSEP mutations, bile flow drops to less than 1% of normal
Solution Approach 1:
The patent uses an intermediary approach by targeting the MDR1 transporter as an alternative pathway for bile acid secretion. Instead of relying on the defective BSEP transporter in PFIC2 patients, the polyhydroxylated bile acids act through MDR1, which remains functional. This intermediary mechanism bypasses the broken BSEP pathway and restores bile flow to clinically beneficial levels.
3Reliability
If polyhydroxylated bile acids with at least four hydroxyl groups are administered, then MDR1 transporter affinity increases, but chemical complexity increases
Solution Approach 1:
The patent systematically changes the chemical parameters of bile acids by introducing multiple hydroxyl groups at specific positions on the steroid nucleus. This controlled parameter change increases affinity for the MDR1 transporter while maintaining a systematic approach to structural modification that allows for predictable synthesis and characterization of the derivatives.
Data Source
AI summary
The invention provides, in part, polyhydroxylated bile acids for treating biliary disorders, for example, biliary disorders arising out of cholestasis of portal hypertension. The invention also provides, in part, polyhydroxylated bile acids for stimulating bile flow. New compounds 2α, 3α, 7α, 12α-tetrahydroxy-5β-cholanoic acid and 3α. 4α, 7α, 12α-tetrahydroxy-5β-cholanoic acid are disclosed, uses thereof and synthesis thereof.