Lead optimization of 5-amino-6-(2,2-dimethyl-5-oxo-4-phenylpiperazin-1-yl)-4-hydroxyhexanamides to reduce a cardiac safety issue: discovery of DS-8108b, an orally active renin inhibitor

Bioorg Med Chem. 2013 Jun 1;21(11):3175-96. doi: 10.1016/j.bmc.2013.03.022. Epub 2013 Mar 26.

Abstract

With the aim to address an undesired cardiac issue observed with our related compound in the recently disclosed novel series of renin inhibitors, further chemical modifications of this series were performed. Extensive structure-activity relationships studies as well as in vivo cardiac studies using the electrophysiology rat model led to the discovery of clinical candidate trans-adamantan-1-ol analogue 56 (DS-8108b) as a potent renin inhibitor with reduced potential cardiac risk. Oral administration of single doses of 3 and 10 mg/kg of 56 in cynomolgus monkeys pre-treated with furosemide led to significant reduction of mean arterial blood pressure for more than 12 h.

MeSH terms

  • Administration, Oral
  • Animals
  • Antihypertensive Agents / chemical synthesis*
  • Antihypertensive Agents / pharmacokinetics
  • Antihypertensive Agents / pharmacology
  • Arrhythmias, Cardiac / prevention & control*
  • Arterial Pressure / drug effects
  • Female
  • Heart / drug effects*
  • Heart / physiopathology
  • Humans
  • Hypertension / drug therapy*
  • Hypertension / enzymology
  • Hypertension / physiopathology
  • Macaca fascicularis
  • Male
  • Organ Culture Techniques
  • Piperazines / chemical synthesis*
  • Piperazines / pharmacokinetics
  • Piperazines / pharmacology
  • Protease Inhibitors / chemical synthesis*
  • Protease Inhibitors / pharmacokinetics
  • Protease Inhibitors / pharmacology
  • Rabbits
  • Rats
  • Renin / antagonists & inhibitors*
  • Renin / chemistry
  • Renin / metabolism
  • Structure-Activity Relationship

Substances

  • Antihypertensive Agents
  • Piperazines
  • Protease Inhibitors
  • Renin