The “induced hyperactivity” test for the de-risking of potential off-target activity of antihypertensive drugs

IntroductionCompound X is a new proprietary antihypertensive agent that induces its pharmacodynamic effect at an approximate plasma Cmax.u of 0.6 nmol/L (rat hypertension model). However, Compound X also shows potent off-target activity at PDE-10a (IC50 ~ 12 nmol/L). Since PDE-10a is expressed predominantly in brain (striatum) and inhibition/knockout of PDE-10a have been reported to result in anti-psychotic effects, we have established the “induced hyperactivity” test for CNS de-risking of Compound X.MethodsMale Wistar rats treated orally with vehicle or Compound X (single dose; 1-3-10 mg/kg) were assessed for exploratory locomotor activity following induction of hyperactivity by d-amphetamine (2 mg/kg) or the NMDA antagonist MK-801 (0.2 mg/kg). The assay was validated with anti-psychotic drugs (haloperidol, clozapine).ResultsInduced hyperactivity was not antagonized by Compound X at doses relevant for its primary pharmacodynamic activity (0.1-0.3 mg/kg, rat). Although sufficient plasma concentrations were reached with Compound X (Cmax.u up to ~ 8 nmol/L at 10 mg/kg) to show its PDE-10a activity, its low brain penetration (~ 10%) likely precluded any meaningful PDE-10a inhibition. In comparison, other blood pressure lowering agents such as prazosin (alpha-1 adrenoceptor antagonist) and isradipine (L-Type Ca2 + channel blocker), but not the NO-donor ISDN, tended to attenuate induced hyperactivity in rats at high doses.ConclusionThe relevance of a potent in-vitro off-target hit (PDE-10a inhibition) by Compound X was attenuated by a robust in-vivo assay (rat induced hyperactivity test), hence lowering the potential liability profile of Compound X. Finally, this piece of investigative safety pharmacology work enabled early de-risking of Compound X based on its primary pharmacodynamic activity in a relevant rat model.