Structural modification of the highly potent peptide bradykinin B1 receptor antagonist B9958

Bradykinin (BK)-related peptides stimulate two major classes of receptors, B1 and B2. The B1 receptor (B1R) plays an important role in various pathophysiological states including chronic inflammation, pain, hypotension, trauma and proliferation of cancer. Therefore, there is interest in the development of highly potent peptide BK B1R antagonists. We previously developed a highly potent and selective BK B1R receptor antagonist, B9958 (Lys-Lys-[Hyp3, CpG5, d-Tic7, CpG8]des-Arg9-BK) (Hyp, trans-4-hydroxyproline; CpG, α-cyclopentylglycine; Tic, tetrahydroisoquinoline-3-carboxylic acid). We now report on new BK B1R antagonist analogs of B9958 with N-terminal basic residues in the d-configuration, or Lys-, Orn- derivatives (NiK, ε-nicotinoyllysine; PzO, 3-pyrazinoylornithine) and/or having hindered unusual amino acids at position 5 (Igl, α-(2-indanyl)glycine). These changes were designed to prevent enzyme degradation while keeping an acceptable affinity. However, these new analogs do not show higher B1R antagonist activity than B9958, but its N-terminal acylated derivative with a bulky and hydrophobic 2,3,4,5,6-pentafluorocinnamic acid (F5c), B10324, retains a B1R antagonist activity close to that of B9958 and, in addition, has high inhibition in vivo against lung cancer (SCLC, 86 %) and moderate inhibition against prostate cancer (PC3, 43%) xenografts. This class of compounds offers hope for the development of new BK antagonist peptide drugs for lung or prostate cancer.