Tricyclic pharmacophore-based molecules as novel integrin α_vβ₃ antagonists. Part 2: Synthesis of potent α_vβ₃/α_IIbβ₃ dual antagonists

We synthesized 4-aminopiperidine derivatives of our prototype integrin α_vβ₃ 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 α_vβ ₃ receptor binding activity. Some of these compounds are novel and potent α_vβ₃/α_IIbβ ₃ dual antagonists with acceptable water solubility and a satisfactory early absorption, distribution, metabolism, excretion, and toxicity (ADMET) profile.