In vitro pharmacological profile of PHA-022121, a small molecule bradykinin B2 receptor antagonist in clinical development

• DOI: 10.1016/j.intimp.2022.108523
• Publication Date: 2022-01-24T17:58:31Z
• Authors: Anne Lesage; François Marceau; Christoph Gibson; Brigitte Loenders; Werner Katzer; Horst-Dieter Ambrosi; Jörn Saupe; Alexander Faussner; Evangelia Pardali; Jochen Knolle
• Keywords: Icatibant; Bradykinin receptor; Competitive antagonist

PHA-022121 is a novel small molecule bradykinin B2 receptor antagonist, in clinical development for the treatment and prevention of hereditary angioedema attacks. The present study describes vitro pharmacological characteristics its active metabolite, PHA-022484 (M2-D). In mammalian cell lines, show high affinity recombinant human with Ki values 0.47 0.70 nM, respectively, potent antagonism Kb 0.15 0.26 respectively (calcium mobilization assay). Antagonist potency at cynomolgus monkey similarly (Kb 1.42 1.12 nM PHA-022484, respectively), however, rat, mouse, rabbit dog receptors least 100-fold lower than both compounds. umbilical vein contractility assay, potent, surmountable reversible antagonist activity pA2 0.35 respectively. off-target profile demonstrates degree selectivity over wide range molecular targets, including B1 receptor. It concluded that novel, low-molecular weight, competitive affinity, potency, selectivity. about 20-fold more icatibant as assessed using or endogenously expressed receptors.