Arylsulfonamide pyrimidines as VLA-4 antagonists

Area of Science:

• Medicinal Chemistry
• Pharmacology
• Immunology

Background:

• Vascular cell adhesion molecule-1 (VLA-4) plays a critical role in inflammatory and autoimmune diseases.
• Targeting VLA-4 offers a therapeutic strategy for various conditions.
• Development of orally available antagonists is desirable for improved patient compliance.

Purpose of the Study:

• To discover and characterize novel, orally available VLA-4 antagonists.
• To evaluate the in vivo efficacy of lead compounds in relevant animal models.
• To assess the in vitro selectivity profile of a representative compound.

Main Methods:

• Synthesis of a series of (S)-2-(2-(diethylamino)-5-(N-alkyl-N-sulfonamido)pyrimidin-4-ylamino)-3-(4-(carbamoyloxy)phenyl)propanoic acid derivatives.
• In vivo testing in multiple animal models to assess therapeutic efficacy.
• In vitro assays to determine the selectivity of the compounds.

Main Results:

• Discovery of a novel series of orally available VLA-4 antagonists.
• Representative compounds, specifically 11b and 11p, demonstrated significant efficacy in vivo.
• Compound 11p exhibited favorable in vitro selectivity.

Conclusions:

• The identified compounds represent promising candidates for the treatment of VLA-4 mediated diseases.
• Oral availability and demonstrated in vivo efficacy support further development.
• The selectivity profile of compound 11p warrants further investigation.