Indolin-2-one p38α inhibitors III: bioisosteric amide replacement
Paul Eastwood1, Jacob González, Elena Gómez
1Almirall Research Center, Almirall Laboratories, Ctra. Laureà Miró 408, E-08980 St. Feliu de Llobregat, Barcelona, Spain. paul.eastwood@almirall.com
Bioorganic & Medicinal Chemistry Letters
|October 1, 2011
Summary
Researchers designed new p38α inhibitors by replacing unstable amide groups with bioisosteric derivatives. Triazole derivative 13 showed good bioavailability and potent in-vivo anti-inflammatory activity.
Area of Science:
- Medicinal Chemistry
- Structural Biology
- Pharmacology
Background:
- Lead series of p38α inhibitors exhibited hydrolytic instability in human liver preparations.
- Amide moiety was identified as a key area for modification to improve drug stability.
- Crystallographic structural data guided the design of novel inhibitor derivatives.
Purpose of the Study:
- To design and synthesize bioisosteric derivatives of p38α inhibitors.
- To replace the hydrolytically unstable amide group with more stable moieties.
- To evaluate the in-vitro and in-vivo efficacy of the novel derivatives.
Main Methods:
- Utilized crystallographic structural information for rational drug design.
- Synthesized a series of bioisosteric derivatives, focusing on triazole replacements.
- Assessed hydrolytic stability in human liver preparations.
- Determined bioavailability in rat models.
- Evaluated in-vivo anti-inflammatory activity in an acute inflammation model.
Main Results:
- Successfully designed and synthesized bioisosteric derivatives to replace the amide moiety.
- Triazole derivative 13 demonstrated improved hydrolytic stability compared to the lead series.
- Triazole derivative 13 exhibited moderate bioavailability in rats.
- Potent in-vivo anti-inflammatory activity was observed for triazole derivative 13.
Conclusions:
- Bioisosteric replacement of the amide moiety is a viable strategy to enhance the stability of p38α inhibitors.
- Triazole derivative 13 represents a promising candidate for further development as an anti-inflammatory agent.
- The study highlights the successful application of structure-based drug design in improving pharmacokinetic and pharmacodynamic properties.
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