Through a directed screening of a combinatorial library containing carboxylic acids, N-sulfonylated dipeptides were identified as leads in the Merck Research Laboratories VLA-4 antagonist program. Further optimization quickly identified subnanomolar compounds with varying degrees of specificity over the related integrin α4β7. Various metabolic liabilities were identified and addressed. However, the pharmacokinetic properties of nearly all compounds in this class were unacceptable. Other leads were identified with apparent good oral bioavailability, but these were generally associated with very high plasma protein binding and a loss of potency. The mechanism of high plasma clearance was identified in the rat as the organic acid transporter, mrp-2. Compounds were identified that were not substrates of mrp-2, but they still suffered from poor oral bioavailability. Finally, a shift in strategy to identifying VLA-4 antagonists that would be suitable as candidates for inhalation therapy resulted in the preparation of compounds with exception tight binding properties. These compounds were superior to BIO-1211 in the ovalbumin-sensitized mouse model of eosinophil trafficking to the lung. One particular compound had an exceptionally long off-rate with a KD ≤ 2 pM. The evolution of the structure activity relationships in our laboratories and strategies for improving potencies and pharmacokinetic profiles are the subject of this review.
Keywords: n-sulfonylated dipeptide, combinatorial library, vla-4 antagonists, sulfonylated phenylalanine derivatives, vla-4 potency, n-arylacetyl-l-biphenylalanine derivatives, n-sulfonylated-prolyl-phenylalanine