Tricyclic pharmacophore-based molecules as novel integrin αvβ3 antagonists. Part 2: Synthesis of potent αvβ3/αIIbβ3 dual antagonists

We synthesized 4-aminopiperidine derivatives of our prototype integrin αvβ3 antagonist 1 in an attempt to increase the activity and water solubility. Introduction of one or two hydrophilic moieties into the central aromatic ring and/or the benzene ring at the C-terminus of 1 increased water solubility and enhanced inhibition of cell adhesion. The results of a structure–activity relationships (SAR) study indicated that the torsion angle between the central aromatic ring and the piperidine ring, and the acidity at the sulfonamide moiety, might be important for αvβ3 receptor binding activity. Some of these compounds are novel and potent αvβ3/αIIbβ3 dual antagonists with acceptable water solubility and a satisfactory early absorption, distribution, metabolism, excretion, and toxicity (ADMET) profile.

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