title: The "induced hyperactivity" test for the de-risking of potential off-target activity of antihypertensive drugs.
abstract: BACKGROUND
  Compound X is a new proprietary antihypertensive agent that induces its pharmacodynamic effect at an approximate plasma Cmax.u of 0.6nmol/L (rat hypertension model). However, Compound X also shows potent off-target activity at PDE-10a (IC50~12nmol/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.
  
  
  METHODS
  Male Wistar rats treated orally with vehicle or Compound X (single dose; 1-3-10mg/kg) were assessed for exploratory locomotor activity following induction of hyperactivity by d-amphetamine (2mg/kg) or the NMDA antagonist MK-801 (0.2mg/kg). The assay was validated with anti-psychotic drugs (haloperidol, clozapine).
  
  
  RESULTS
  Induced hyperactivity was not antagonized by Compound X at doses relevant for its primary pharmacodynamic activity (0.1-0.3mg/kg, rat). Although sufficient plasma concentrations were reached with Compound X (Cmax.u up to ~8nmol/L at 10mg/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 Ca(2+) channel blocker), but not the NO-donor ISDN, tended to attenuate induced hyperactivity in rats at high doses.
  
  
  CONCLUSIONS
  The 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.
authors.affiliation: BPH-DD-ED-TOX, Safety Pharmacology, Bayer Pharma AG, Aprather Weg 18a, D-42096 Wuppertal, Germany. Electronic address: herbert.himmel@bayer.com.
authors.forename: Herbert M
authors.initials: HM
authors.lastname: Himmel
authors.affiliation: BPH-DD-ED-TOX, Safety Pharmacology, Bayer Pharma AG, Aprather Weg 18a, D-42096 Wuppertal, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Hoffmann
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000493:pharmacokinetics / Q000633:toxicity*; D014150:Antipsychotic Agents / Q000633:toxicity; D001794:Blood Pressure / Q000187:drug effects; D001921:Brain / Q000378:metabolism; D000697:Central Nervous System Stimulants / Q000633:toxicity; D003913:Dextroamphetamine / Q000633:toxicity; D016291:Dizocilpine Maleate / Q000633:toxicity; D004353:Drug Evaluation, Preclinical; D018691:Excitatory Amino Acid Antagonists / Q000633:toxicity; D005106:Exploratory Behavior / Q000187:drug effects; D006948:Hyperkinesis / Q000139:chemically induced* / Q000523:psychology*; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000959:Antihypertensive Agents; D014150:Antipsychotic Agents; D000697:Central Nervous System Stimulants; D018691:Excitatory Amino Acid Antagonists; D016291:Dizocilpine Maleate; D003913:Dextroamphetamine
keywords: (+)-MK-801; Blood pressure; Central nervous system; Locomotor activity; NMDA antagonist; Off-target activity; Rat; Reference compounds; d-Amphetamine; “Induced hyperactivity” method