ABSTRACT
One small molecule inhibitor of αvß1 integrin, c8, shows antifibrotic effects in multiple in vivo mouse models. Here we synthesized c8 analogues and systematically investigate their structure-activity relationships (SAR) in αvß1 integrin inhibition. N-Phenylsulfonyl-l-homoproline analogues of c8 maintained excellent potency against αvß1 integrin while retaining good selectivity over other RGD integrins. In addition, 2-aminopyridine or cyclic guanidine analogues were shown to be equally potent to c8. A rigid phenyl linker increased the potency compared to c8, but the selectivity over other RGD integrins diminished. These results can provide further insights on design of αvß1 integrin inhibitors as antifibrotics.
ABSTRACT
Starting from chiral-protected 4-hydroxymethyl pyrrolidin-2-ones, the otherwise elusive 3,4-trans-3,3,4-trisubstituted isosteres of α-methyl homoserine, tethered on a γ-lactam ring, were prepared exploiting stereoselective electrophilic aminations. These reactions led to the isolation and characterization of a novel type of atropisomers, exceedingly stable at room temperature, that were directly converted to the desired products by a novel non-reductive N-N bond cleavage reaction.
Subject(s)
Homoserine/analogs & derivatives , Homoserine/chemical synthesis , Lactams/chemistry , Amination , Homoserine/chemistry , Molecular Conformation , Molecular Structure , StereoisomerismABSTRACT
Starting from a chiral 4-hydroxymethyl pyrrolidin-2-one, an isostere of α-methyl homoserine tethered on a γ-lactam ring was prepared exploiting a stereoselective acylation-methylation sequence, followed by Curtius rearrangement, and structural assignment was confirmed by n.O.e. experiments. By reverting the sequence, the 3-carboxy-3-methyl derivative having the opposite configuration at C-3 was obtained with total stereoselection, but Curtius rearrangement invariably afforded only inseparable mixtures of decomposition products.
