Efficient synthesis of 3-aminocyclobut-2-en-1-ones: squaramide surrogates as potent VLA-4 antagonists.

A novel series of uniquely functionalized 3-aminocyclobut-2-en-1-ones has been prepared by facile condensation of a variety of cyclobuta-1,3-diones with a phenylalanine-derived primary amine. These systems subsequently lend themselves to substitution at C-2 by reaction with a variety of electrophilic reagents including N-halosuccinimides, sulfenyl chlorides, and Eschenmoser's salt. Compounds from this novel series are potent antagonists of VLA-4.

Dehydrophenylalanine derivatives as VLA-4 integrin antagonists.

We describe a series of dehydrophenylalanine derivatives where the Z isomers are potent VLA-4 antagonists but are subject to rapid biliary clearance and the E isomers have poor activity but have a slower rate of clearance. These configurationally constrained molecules have led to the design of a novel class of benzodiazepine VLA-4 antagonists.

N-(pyrimidin-4-yl) and N-(pyridin-2-yl) phenylalanine derivatives as VLA-4 integrin antagonists.

The SAR studies to optimise both potency and rate of clearance in the rat for a series of pyrimidine and pyridine based VLA-4 antagonists are described.

Discovery and evaluation of N-(triazin-1,3,5-yl) phenylalanine derivatives as VLA-4 integrin antagonists.

SAR studies aimed at improving the rate of clearance of a series of VLA-4 integrin antagonists by the introduction of a 1,3,5-triazine as an amide isostere are described.