Advanced Lenalidomide Derivatives for PROTAC Optimization
Advanced Lenalidomide Derivatives for PROTAC Optimization
While the primary API and common impurities are essential for basic R&D, these seven products provide the precision needed for pharmacokinetic (PK) modeling and advanced synthetic methodology.
1. Lenalidomide Hydrochloride
CAS No: 1243329-97-6
Technical Role: The salt form of Lenalidomide offers significantly improved aqueous solubility compared to the free base. For researchers developing oral PROTAC formulations, using the HCl salt as a starting point helps in predicting the dissolution profile and bioavailability of the final chimeric molecule.
2. (R)-Lenalidomide (The Chiral Impurity)
CAS No: 119313-12-1 (approx. for R-isomer)
Technical Role: Lenalidomide is typically a racemic mixture, but the enantiomers exhibit different biological potencies. The (R)-isomer is often treated as a chiral impurity. In PROTAC design, stereochemistry is a "make or break" factor for ternary complex stability; having the isolated (R)-isomer allows chemists to prove that their degrader’s activity is truly stereospecific.
3. Lenalidomide 5-Amino Impurity
CAS No: 191732-74-8
Technical Role: This structural isomer (where the amino group is at the 5-position instead of the 4-position) is a critical "regioisomeric impurity." Because E3 ligase binding is highly sensitive to the position of substituents on the isoindolinone ring, this compound is used to validate that the PROTAC is binding via the intended 4-amino orientation.
4. N-Acetyl Lenalidomide
CAS No: 1421593-80-7
Technical Role: Acetylation is a common metabolic pathway and a process impurity. For PROTACs, the amino group is usually the site of linker attachment. If this group is acetylated during synthesis, it blocks linker conjugation. Monitoring this impurity ensures high coupling efficiency during the "click chemistry" or amide-coupling stages of PROTAC assembly.
5. Lenalidomide 2-(Oxoisoindolinyl) Oxopentanoic Acid
CAS No: 2197420-75-8 (Related Compound C)
Technical Role: Also known as a "Diamide" or "Related Compound C," this molecule is a primary indicator of oxidative stress or forced degradation. In stability studies of PROTAC candidates, the presence of this compound signals that the glutarimide "hook" is breaking down, which would lead to a loss of Cereblon recruitment in vivo.
6. Lenalidomide Open Ring Bis-Methyl Ester
CAS No: 1198299-50-1
Technical Role: This is a sophisticated process impurity arising from the use of methanol during synthesis. It serves as a marker for solvent-solute interactions. For process chemists, controlling this impurity is vital during the scale-up of PROTAC intermediates to ensure the final product meets international regulatory standards (ICH).
7. 3-Aminopiperidine-2,6-dione Hydrochloride
CAS No: 24666-56-6
Technical Role: This is the "glutarimide moiety" itself, separate from the isoindolinone ring. It is used as a high-purity building block for researchers who wish to synthesize novel Cereblon ligands from scratch rather than using the standard Lenalidomide scaffold. It is the "gold standard" reagent for creating custom E3 ligase recruiters.
Comparative Technical Data Table
| Product Name | CAS Number | Molecular Formula | Importance in TPD |
|---|---|---|---|
| Lenalidomide HCl | 1243329-97-6 | C13H14ClN3O3 | Enhanced solubility for PK studies. |
| (R)-Lenalidomide | 191732-72-6 (rac) | C13H13N3O3 | Stereochemical purity validation. |
| 5-Amino Impurity | 191732-74-8 | C13H13N3O3 | Regioisomeric control for binding. |
| N-Acetyl Derivative | 1421593-80-7 | C15H15N3O4 | Conjugation efficiency marker. |
| Related Compound C | 2197420-75-8 | C13H15N3O4 | Forced degradation & stability testing. |
| Bis-Methyl Ester | 1198299-50-1 | C15H18N2O5 | Process-related solvent interaction marker. |
| Glutarimide Block | 24666-56-6 | C5H9ClN2O2 | Custom E3 ligand synthesis. |
Industry Outlook: Why Demand Continues to Grow
- ✔ Rising number of PROTACs in clinical pipelines
- ✔ Increased regulatory focus on impurity control
- ✔ Shift toward precision degradation strategies
- ✔ Expansion beyond oncology into neurology and immunology
Lenalidomide-based products remain indispensable tools for advancing targeted protein degradation.
Why Choose Pharmaffiliates for These Advanced Standards?
Precision in TPD research requires more than just "99% purity." It requires a deep understanding of how an impurity affects the ternary complex.
Structural Certainty: Every derivative is backed by 1H-NMR, 13C-NMR, and Mass Spectrometry.
Regulatory Ready: Our standards help you navigate ANDA and DMF filings with ease.
Global Reach: Rapid supply of rare impurities like the Bis-Methyl Ester and 5-Amino variants.
Conclusion: Supporting the Full PROTAC Lifecycle
From click-ready intermediates and fluorinated derivatives to chiral materials and impurity standards, these seven lenalidomide-based products play a vital role across discovery, optimization, and regulatory development of PROTAC therapeutics.
High-purity, well-characterized CRBN ligands are no longer optional, they are foundational to successful protein degrader programs.
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