Investigational Drug Details

Drug ID: D267
Drug Name: Perindopril
Synonyms: (2S,3aS,7aS)-1-[(2S)-2-{[(2S)-1-ethoxy-1-oxopentan-2-yl]amino}propanoyl]octahydro-1H-indole-2-carboxylic acid; Perindopril
Type: Chemical drug
DrugBank ID: DB00790
DrugBank Description: Perindopril is a nonsulfhydryl prodrug that belongs to the angiotensin-converting enzyme (ACE) inhibitor class of medications. It is rapidly metabolized in the liver to perindoprilat, its active metabolite, following oral administration. Perindoprilat is a potent, competitive inhibitor of ACE, the enzyme responsible for the conversion of angiotensin I (ATI) to angiotensin II (ATII). ATII regulates blood pressure and is a key component of the renin-angiotensin-aldosterone system (RAAS). Perindopril may be used to treat mild to moderate essential hypertension, mild to moderate congestive heart failure, and to reduce the cardiovascular risk of individuals with hypertension or post-myocardial infarction and stable coronary disease.
PubChem ID: 107807
CasNo: 82834-16-0
Repositioning for NAFLD: Yes
SMILES: C(=O)([C@@H](N[C@H](C(=O)OCC)CCC)C)N1[C@@H]2[C@H](C[C@H]1C(=O)O)CCCC2
Structure:
InChiKey: IPVQLZZIHOAWMC-QXKUPLGCSA-N
Molecular Weight: 368.474
DrugBank Targets: Angiotensin-converting enzyme inhibitor; Secreted frizzled-related protein 4 inhibitor
DrugBank MoA: There are two isoforms of ACE: the somatic isoform, which exists as a glycoprotein comprised of a single polypeptide chain of 1277; and the testicular isoform, which has a lower molecular mass and is thought to play a role in sperm maturation and binding of sperm to the oviduct epithelium. Somatic ACE has two functionally active domains, N and C, which arise from tandem gene duplication. Although the two domains have high sequence similarity, they play distinct physiological roles. The C-domain is predominantly involved in blood pressure regulation while the N-domain plays a role in hematopoietic stem cell differentiation and proliferation. ACE inhibitors bind to and inhibit the activity of both domains, but have much greater affinity for and inhibitory activity against the C-domain. Perindoprilat, the active metabolite of perindopril, competes with ATI for binding to ACE and inhibits and enzymatic proteolysis of ATI to ATII. Decreasing ATII levels in the body decreases blood pressure by inhibiting the pressor effects of ATII as described in the Pharmacology section above. Perindopril also causes an increase in plasma renin activity likely due to a loss of feedback inhibition mediated by ATII on the release of renin and/or stimulation of reflex mechanisms via baroreceptors.
DrugBank Pharmacology: Perindopril is a nonsulfhydryl prodrug that is metabolized via first pass effect (62%) and systemic hydrolysis (38%) to perindoprilat, its active metabolite, following oral administration. Perindoprilat lowers blood pressure by antagonizing the effect of the RAAS. The RAAS is a homeostatic mechanism for regulating hemodynamics, water and electrolyte balance. During sympathetic stimulation or when renal blood pressure or blood flow is reduced, renin is released from the granular cells of the juxtaglomerular apparatus in the kidneys. In the blood stream, renin cleaves circulating angiotensinogen to ATI, which is subsequently cleaved to ATII by ACE. ATII increases blood pressure using a number of mechanisms. First, it stimulates the secretion of aldosterone from the adrenal cortex. Aldosterone travels to the distal convoluted tubule (DCT) and collecting tubule of nephrons where it increases sodium and water reabsorption by increasing the number of sodium channels and sodium-potassium ATPases on cell membranes. Second, ATII stimulates the secretion of vasopressin (also known as antidiuretic hormone or ADH) from the posterior pituitary gland. ADH stimulates further water reabsorption from the kidneys via insertion of aquaporin-2 channels on the apical surface of cells of the DCT and collecting tubules. Third, ATII increases blood pressure through direct arterial vasoconstriction. Stimulation of the Type 1 ATII receptor on vascular smooth muscle cells leads to a cascade of events resulting in myocyte contraction and vasoconstriction. In addition to these major effects, ATII induces the thirst response via stimulation of hypothalamic neurons. ACE inhibitors inhibit the rapid conversion of ATI to ATII and antagonize RAAS-induced increases in blood pressure. ACE (also known as kininase II) is also involved in the enzymatic deactivation of bradykinin, a vasodilator. Inhibiting the deactivation of bradykinin increases bradykinin levels and may sustain the effects of perindoprilat by causing increased vasodilation and decreased blood pressure.
DrugBank Indication: For the treatment of mild to moderate essential hypertension, mild to moderate congestive heart failure, and to reduce the cardiovascular risk of individuals with hypertension or post-myocardial infarction and stable coronary disease.
Targets: ACE inhibitor
Therapeutic Category: Antihypertensive drug
Clinical Trial Progress: Clinical trial on-going (ChiCTR-TRC-14005028)
Latest Progress: Under clinical trials

Trial ID Source ID Phases Status Study Results Start Date Last Update Posted
L0029 NCT02213224 Phase 4 Unknown status No Results Available August 2014 August 11, 2014 Details
L0628 ChiCTR-TRC-14005028 Phase 1 Recruiting No Results Available 30/07/2014 18 April 2017 Details

Target ID Target Name GENE Action Class UniProtKB ID Entry Name
T03 Peroxisome proliferator-activated receptor alpha PPARA agonist Nuclear hormone receptor Q07869 PPARA_HUMAN Details
T21 Diacylglycerol O-acyltransferase 2 DGAT2 inhibitor Enzyme Q96PD7 DGAT2_HUMAN Details
T07 Bile acid receptor NR1H4 agonist Nuclear hormone receptor Q96RI1 NR1H4_HUMAN Details

Strategy ID Strategy Synonyms Related Targets Related Drugs

Article ID PMID Source Title
A19692 26407654 Eur J Pharmacol Perindopril and barnidipine alone or combined with simvastatin on hepatic steatosis and inflammatory parameters in hypertensive patients. Details
A21405 25346221 J Biophotonics Raman spectroscopy analysis of lipid droplets content, distribution and saturation level in Non-Alcoholic Fatty Liver Disease in mice. Details
A27509 18239590 Obesity (Silver Spring) ACE inhibition and AT1 receptor blockade prevent fatty liver and fibrosis in obese Zucker rats. Details