Macrocyclic Lactone Derivatives for Enhanced Bioavailability
Solution Overview
Problem
Rapamycin's low bioavailability and high immunosuppressive potency, along with its potential toxicity, limit its utility as a pharmaceutical drug, and its low water solubility complicates its therapeutic applications.
Innovation Solution
Development of novel macrocyclic lactones with specific chemical modifications, such as demethylation, hydroxylation, epoxidation, and N-oxidation, which are synthesized chemically or biologically to preserve immunosuppressive and anti-proliferative properties, and their use in pharmaceutical compositions for systemic and site-specific therapeutic applications.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If rapamycin is used as a pharmaceutical drug, then immunosuppressive and anti-proliferative therapeutic effects are achieved, but bioavailability is very low and variable
Solution Approach 1:
The patent applies parameter changes by modifying the chemical structure of rapamycin through demethylation, hydroxylation, epoxidation, and N-oxidation at specific positions. These structural modifications alter the physicochemical properties of the molecule, particularly improving its solubility and bioavailability while preserving the immunosuppressive and anti-proliferative therapeutic effects through maintained binding affinity to mTOR and other target proteins.
2Reliability
If rapamycin is used as a pharmaceutical drug, then immunosuppressive potency is achieved, but toxicity is high
Solution Approach 1:
The patent applies local quality by introducing specific functional groups at particular positions on the rapamycin macrocyclic ring structure. These localized modifications (demethylation at C-4, hydroxylation at C-11 or C-16, epoxidation at C-26/C-27, N-oxidation at C-42) selectively improve solubility and reduce toxicity without compromising the essential pharmacophore regions required for immunosuppressive activity.
3Reliability
If rapamycin is used as a pharmaceutical drug, then therapeutic effects are achieved, but water solubility is very low
Solution Approach 1:
The patent applies parameter changes by introducing polar functional groups (hydroxyl, carboxyl, amino groups) through chemical modifications such as hydroxylation and N-oxidation. These modifications increase the polarity and hydrogen-bonding capacity of the rapamycin derivative molecules, thereby significantly improving their water solubility while maintaining the macrocyclic lactone structure essential for biological activity.
Data Source
AI summary
A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of the formula:wherein R1, R2, R3, R5, R6, R8, M1, M2, M3, M4, M5, M6 and M7 are each independently a member selected from the group consisting of H, C1-6 alkyl, OH and C1-6 hydroxyalkyl; R4, R7 and R9 are each independently selected from the group consisting of C1-6 alkoxy and OH; R10 is a member selected from the group consisting of H, —OH, —OP(O)Me2,—O—(CH2)n—OH and —O—(CH2)m—O—(CH2)o—CH3, wherein subscripts n and m are each independently from 2 to 8 and subscript o is from 1 to 6; each of L1 and L4 are independently selected from the group consisting of:wherein each M8 is independently a member selected from the group consisting of C1-6 alkyl, OH and C1-6 hydroxyalkyl; each of L2 and L3 are independently selected from the group consisting of:andsalts, isomers, or N-oxides thereof.