Thiazole-Based IL-17 Inhibitors Discovered by Scaffold Morphing

Area of Science:

• Medicinal Chemistry
• Immunology
• Drug Discovery

Background:

• Interleukin-17A (IL-17) is crucial for immunity but implicated in inflammatory diseases like psoriasis.
• Current treatments include IL-17 antibodies, but low molecular weight inhibitors are sought.
• Psoriasis treatment is an active area of pharmaceutical research.

Purpose of the Study:

• To discover and develop novel, low molecular weight inhibitors of IL-17.
• To explore a scaffold-morphing strategy for generating potent IL-17 inhibitors.
• To assess the pharmacokinetic and safety profiles of new thiazole-based compounds.

Main Methods:

• Utilized a scaffold-morphing strategy involving ring-opening of a known scaffold.
• Employed a chalcogen interaction to maintain molecular conformation.
• Synthesized and optimized thiazole-based compounds.
• Evaluated compound potency, oral exposure in rats, and tolerability.

Main Results:

• Discovered potent IL-17 inhibitors based on a novel thiazole scaffold.
• Optimized compounds 11 and 15 exhibited good oral exposure in rats.
• Compound 11 showed no adverse effects in a rat tolerability study at high doses.
• The developed compounds demonstrated a good overall profile.

Conclusions:

• The scaffold-morphing strategy successfully yielded potent IL-17 inhibitors.
• Thiazole-based compounds represent a promising new class of IL-17 inhibitors.
• Optimized compounds possess favorable pharmacokinetic and safety profiles for potential therapeutic use.