The discovery and potential of N-sulfonylated dipeptide VLA-4 antagonists.

摘要: Through a directed screening of combinatorial library containing carboxylic acids, N-sulfonylated dipeptides were identified as leads in the Merck Research Laboratories VLA-4 antagonist program. Further optimization quickly subnanomolar compounds with varying degrees specificity over related integrin alpha4beta7. Various metabolic liabilities and addressed. However, pharmacokinetic properties nearly all this class unacceptable. Other apparent good oral bioavailability, but these generally associated very high plasma protein binding loss potency. The mechanism clearance was rat organic acid transporter, mrp-2. Compounds that not substrates mrp-2, they still suffered from poor bioavailability. Finally, shift strategy to identifying antagonists would be suitable candidates for inhalation therapy resulted preparation exception tight properties. These superior BIO-1211 ovalbumin-sensitized mouse model eosinophil trafficking lung. One particular compound had an exceptionally long off-rate KD < or = 2 pM. evolution structure activity relationships our laboratories strategies improving potencies profiles are subject review.