ALISKIREN

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C30H53N3O6
Molecular Weight	551.7583
Optical Activity	UNSPECIFIED
Defined Stereocenters	4 / 4
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

COCCCOC1=CC(C[C@@H](C[C@H](N)[C@@H](O)C[C@@H](C(C)C)C(=O)NCC(C)(C)C(N)=O)C(C)C)=CC=C1OC

InChI

InChIKey=UXOWGYHJODZGMF-QORCZRPOSA-N

InChI=1S/C30H53N3O6/c1-19(2)22(14-21-10-11-26(38-8)27(15-21)39-13-9-12-37-7)16-24(31)25(34)17-23(20(3)4)28(35)33-18-30(5,6)29(32)36/h10-11,15,19-20,22-25,34H,9,12-14,16-18,31H2,1-8H3,(H2,32,36)(H,33,35)/t22-,23-,24-,25-/m0/s1

HIDE SMILES / InChI

Molecular Formula	C30H53N3O6
Molecular Weight	551.7583
Charge	0
Count

Stereochemistry	ABSOLUTE
Additional Stereochemistry	No
Defined Stereocenters	4 / 4
E/Z Centers	0
Optical Activity	UNSPECIFIED

Description
Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021985s023lbl.pdf | https://www.ncbi.nlm.nih.gov/pubmed/21687346

Aliskiren – the only direct renin inhibitor which is clinically used as an antihypertensive drug. Aliskiren is the first of a new class of antihypertensive agents. Aliskiren is a new renin inhibitor of a novel structural class that has recently been shown to be efficacious in hypertensive patients after once-daily oral dosing. In short-term studies, it was effective in lowering blood pressure either alone or in combination with valsartan and hydrochlorothiazide, and had a low incidence of serious adverse effects. It was approved by the Food and Drug Administration in 2007 for the use as a monotherapy or in combination with other antihypertensives. Aliskiren is marketed under the trade name Tekturna. Aliskiren effectively reduces functional plasma renin activity by binding to renin with high affinity, preventing it from converting angiotensinogen to angiotensin I. The inhibition of renin by aliskiren is associated with a reduction in circulating levels of angiotensin I and II, with a resultant increase in plasma renin concentration and inhibit activation of mitogen-activated protein kinases ERK1 (p44) and ERK2 (p42).

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Renin 7 Target ID: CHEMBL286 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021985s023lbl.pdf \| https://www.ncbi.nlm.nih.gov/pubmed/18611061	Inhibitor 8297		0.6 nM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Hypertension 567 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021985s023lbl.pdf	Primary		Approved 8429	TEKTURNA Approved Use Amturnide is indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes, including amlodipine and hydrochlorothiazide (HCTZ). There are no controlled trials demonstrating risk reduction with Amturnide. Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than 1 drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program’s Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC). Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality have also been seen regularly. Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (e.g., patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal. Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy. This fixed combination drug is not indicated for initial therapy of hypertension. Amturnide is a combination of aliskiren, a renin inhibitor, amlodipine besylate, a dihydropyridine calcium channel blocker, and hydrochlorothiazide (HCTZ), a thiazide diuretic. Amturnide is indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions: Not indicated for initial therapy. (1) Launch Date 2007

C_max

Value	Dose	Analyte	Population
290.2 ng/mL REVIEW https://pubmed.ncbi.nlm.nih.gov/18611061/	300 mg single, oral dose: 300 mg route of administration: Oral experiment type: SINGLE co-administered:	ALISKIREN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FED
102 ng/mL Clinical Trial https://clinicaltrials.gov/ct2/show/NCT01570686	300 mg 1 times / day steady, oral dose: 300 mg route of administration: oral experiment type: steady co-administered:	ALISKIREN plasma	Homo sapiens population: unhealthy age: sex: food status: Fed
108 ng/mL Clinical Trial https://clinicaltrials.gov/ct2/show/NCT01570686	300 mg 1 times / day steady, oral dose: 300 mg route of administration: oral experiment type: steady co-administered:	ALISKIREN plasma	Homo sapiens population: unhealthy age: sex: food status: Fed
252 ng/mL Clinical Trial https://clinicaltrials.gov/ct2/show/NCT01570686	300 mg 1 times / day steady, oral dose: 300 mg route of administration: oral experiment type: steady co-administered:	ALISKIREN plasma	Homo sapiens population: unhealthy age: sex: food status: Fasted
273 ng/mL Clinical Trial https://clinicaltrials.gov/ct2/show/NCT01570686	300 mg 1 times / day steady, oral dose: 300 mg route of administration: oral experiment type: steady co-administered:	ALISKIREN plasma	Homo sapiens population: unhealthy age: sex: food status: Fasted

AUC

Value	Dose	Analyte	Population
1399 ng × h/mL REVIEW https://pubmed.ncbi.nlm.nih.gov/18611061/	300 mg single, oral dose: 300 mg route of administration: Oral experiment type: SINGLE co-administered:	ALISKIREN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FED
1100 ng*h/mL Clinical Trial https://clinicaltrials.gov/ct2/show/NCT01570686	300 mg 1 times / day steady, oral dose: 300 mg route of administration: oral experiment type: steady co-administered:	ALISKIREN plasma	Homo sapiens population: unhealthy age: sex: food status: Fed
1540 ng*h/mL Clinical Trial https://clinicaltrials.gov/ct2/show/NCT01570686	300 mg 1 times / day steady, oral dose: 300 mg route of administration: oral experiment type: steady co-administered:	ALISKIREN plasma	Homo sapiens population: unhealthy age: sex: food status: Fasted
1580 ng*h/mL Clinical Trial https://clinicaltrials.gov/ct2/show/NCT01570686	300 mg 1 times / day steady, oral dose: 300 mg route of administration: oral experiment type: steady co-administered:	ALISKIREN plasma	Homo sapiens population: unhealthy age: sex: food status: Fasted
872 ng*h/mL Clinical Trial https://clinicaltrials.gov/ct2/show/NCT01570686	300 mg 1 times / day steady, oral dose: 300 mg route of administration: oral experiment type: steady co-administered:	ALISKIREN plasma	Homo sapiens population: unhealthy age: sex: food status: Fed

T_1/2

Value	Dose	Co-administered	Analyte	Population
41 h REVIEW https://pubmed.ncbi.nlm.nih.gov/18611061/	300 mg single, oral dose: 300 mg route of administration: Oral experiment type: SINGLE co-administered:		ALISKIREN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FED

Doses

Dose	Population	Adverse events
600 mg single, oral Highest studied dose Dose: 600 mg Route: oral Route: single Dose: 600 mg Sources: https://pubmed.ncbi.nlm.nih.gov/18538111	healthy, 18 - 45 n = 8 Health Status: healthy Age Group: 18 - 45 Sex: M+F Population Size: 8 Sources: https://pubmed.ncbi.nlm.nih.gov/18538111	Sources: https://pubmed.ncbi.nlm.nih.gov/18538111
600 mg 1 times / day multiple, oral Highest studied dose Dose: 600 mg, 1 times / day Route: oral Route: multiple Dose: 600 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/17367658 Page: p.1161	unhealthy, 53 n = 166 Health Status: unhealthy Condition: Hypertension Age Group: 53 Sex: M+F Population Size: 166 Sources: https://pubmed.ncbi.nlm.nih.gov/17367658 Page: p.1161	Disc. AE: Diarrhea... AEs leading to discontinuation/dose reduction: Diarrhea (0.6%) Sources: https://pubmed.ncbi.nlm.nih.gov/17367658 Page: p.1161
300 mg 1 times / day multiple, oral Recommended Dose: 300 mg, 1 times / day Route: oral Route: multiple Dose: 300 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021985s023lbl.pdf Page: p.1	unhealthy Health Status: unhealthy Condition: Hypertension Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021985s023lbl.pdf Page: p.1	Disc. AE: Disorder fetal, Angioedema... AEs leading to discontinuation/dose reduction: Disorder fetal Angioedema Angioedema Hypotension Impaired renal function Hyperkalemia Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021985s023lbl.pdf Page: p.1
150 mg 1 times / day steady, oral Dose: 150 mg, 1 times / day Route: oral Route: steady Dose: 150 mg, 1 times / day Sources: https://clinicaltrials.gov/ct2/show/NCT01437943	unhealthy n = 7 Health Status: unhealthy Condition: Kidney Transplant Population Size: 7 Sources: https://clinicaltrials.gov/ct2/show/NCT01437943	Other AEs: GI bleed, Knee hemarthrosis... Other AEs: GI bleed (serious, 1 patient) Knee hemarthrosis (serious, 1 patient) Diarrhea (below serious, 5 patients) Lower extremities weakness of (below serious, 1 patient) Sources: https://clinicaltrials.gov/ct2/show/NCT01437943
300 mg 1 times / day steady, oral Dose: 300 mg, 1 times / day Route: oral Route: steady Dose: 300 mg, 1 times / day Sources: https://clinicaltrials.gov/ct2/show/NCT00768040	unhealthy n = 20 Health Status: unhealthy Condition: diabetic macular edema Population Size: 20 Sources: https://clinicaltrials.gov/ct2/show/NCT00768040	Other AEs: Cellulitis, Pneumonia... Other AEs: Cellulitis (serious, 1 patient) Pneumonia (serious, 1 patient) Diabetic foot (serious, 1 patient) Choroidal neovascularisation (below serious, 1 patient) Foreign body sensation in eyes (below serious, 1 patient) Asteroid hyalosis (below serious, 1 patient) Retinal neovascularisation (below serious, 1 patient) Vision blurred (below serious, 1 patient) Vitreous detachment (below serious, 1 patient) Diarrhoea (below serious, 1 patient) Flatulence (below serious, 1 patient) Fatigue (below serious, 1 patient) Fungal skin infection (below serious, 1 patient) Respiratory tract infection (below serious, 1 patient) Sinusitis (below serious, 1 patient) Tooth fracture (below serious, 1 patient) Hypoglycaemia (below serious, 1 patient) Arthritis (below serious, 1 patient) Muscle spasms (below serious, 1 patient) Myalgia (below serious, 1 patient) Pain in extremity (below serious, 1 patient) Pain in jaw (below serious, 1 patient) Basal cell carcinoma (below serious, 2 patients) Paraesthesia (below serious, 1 patient) Epistaxis (below serious, 1 patient) Hypotension (below serious, 2 patients) Sources: https://clinicaltrials.gov/ct2/show/NCT00768040
300 mg 1 times / day steady, oral (max) Dose: 300 mg, 1 times / day Route: oral Route: steady Dose: 300 mg, 1 times / day Sources: https://clinicaltrials.gov/ct2/show/NCT00894387	unhealthy n = 808 Health Status: unhealthy Condition: acute decompensated Heart Failure Population Size: 808 Sources: https://clinicaltrials.gov/ct2/show/NCT00894387	Other AEs: Anaemia, Haemorrhagic disorder... Other AEs: Anaemia (serious, 6 patients) Haemorrhagic disorder (serious, 1 patient) Hilar lymphadenopathy (serious, 1 patient) Lymphadenopathy (serious, 1 patient) Splenic infarction (serious, 1 patient) Angina unstable (serious, 7 patients) Aortic valve incompetence (serious, 1 patient) Arteriospasm coronary (serious, 1 patient) Atrial flutter (serious, 3 patients) Atrioventricular block complete (serious, 2 patients) Cardio-respiratory arrest (serious, 7 patients) Cardiogenic shock (serious, 7 patients) Cardiomyopathy (serious, 1 patient) Cardiopulmonary failure (serious, 2 patients) Coronary artery disease (serious, 4 patients) Left ventricular dysfunction (serious, 1 patient) Low cardiac output syndrome (serious, 1 patient) Fibrosis myocardial (serious, 1 patient) Tachyarrhythmia (serious, 1 patient) Tachycardia (serious, 3 patients) Ventricular extrasystoles (serious, 1 patient) Ventricular tachycardia (serious, 10 patients) Vertigo (serious, 4 patients) Cataract (serious, 3 patients) Retinal detachment (serious, 1 patient) Constipation (serious, 2 patients) Duodenal ulcer haemorrhage (serious, 1 patient) Enterocolitis (serious, 1 patient) Gastritis (serious, 1 patient) Hiatus hernia (serious, 1 patient) Intestinal obstruction (serious, 1 patient) Intestinal polyp (serious, 1 patient) Nausea (serious, 8 patients) Small intestinal obstruction (serious, 1 patient) Umbilical hernia, obstructive (serious, 1 patient) Upper gastrointestinal haemorrhage (serious, 1 patient) Vomiting (serious, 5 patients) Chest discomfort (serious, 1 patient) Chest pain (serious, 6 patients) Device lead issue (serious, 1 patient) Drug intolerance (serious, 1 patient) Necrosis (serious, 1 patient) Non-cardiac chest pain (serious, 7 patients) Soft tissue inflammation (serious, 1 patient) Sudden death (serious, 9 patients) Cholecystitis (serious, 2 patients) Hepatic cirrhosis (serious, 1 patient) Hepatic cyst (serious, 1 patient) Hepatorenal syndrome (serious, 1 patient) Heart transplant rejection (serious, 1 patient) Anal abscess (serious, 1 patient) Appendicitis (serious, 2 patients) Bronchitis bacterial (serious, 1 patient) Erysipelas (serious, 2 patients) Gastrointestinal viral infection (serious, 1 patient) Hepatitis B (serious, 1 patient) Liver abscess (serious, 1 patient) Infection localised (serious, 1 patient) Lower respiratory tract infection (serious, 3 patients) Orchitis (serious, 1 patient) Osteomyelitis acute (serious, 1 patient) Paronychia (serious, 1 patient) Pseudomembranous colitis (serious, 2 patients) Respiratory tract infection (serious, 3 patients) Sepsis (serious, 8 patients) Viral infection (serious, 1 patient) Wound infection pseudomonas (serious, 1 patient) Accidental overdose (serious, 1 patient) Ankle fracture (serious, 1 patient) Contusion (serious, 1 patient) Dermatitis artefacta (serious, 1 patient) Electric shock (serious, 1 patient) Extradural haematoma (serious, 1 patient) Femoral neck fracture (serious, 1 patient) Femur fracture (serious, 4 patients) Head injury (serious, 1 patient) Humerus fracture (serious, 2 patients) Laceration (serious, 1 patient) Post procedural haematoma (serious, 1 patient) Procedural haemorrhage (serious, 1 patient) Pubis fracture (serious, 1 patient) Spinal compression fracture (serious, 1 patient) Splenic rupture (serious, 1 patient) Subdural haematoma (serious, 2 patients) Thermal burn (serious, 1 patient) Toxicity to various agents (serious, 2 patients) Blood creatinine increased (serious, 3 patients) Haemoglobin decreased (serious, 1 patient) International normalised ratio increased (serious, 2 patients) Renal function test abnormal (serious, 1 patient) Decreased appetite (serious, 1 patient) Diabetic ketoacidosis (serious, 1 patient) Failure to thrive (serious, 1 patient) Fluid intake reduced (serious, 1 patient) Hypoglycaemia (serious, 7 patients) Arthralgia (serious, 1 patient) Arthritis (serious, 1 patient) Bursitis (serious, 1 patient) Costochondritis (serious, 1 patient) Joint effusion (serious, 1 patient) Muscular weakness (serious, 1 patient) Pain in extremity (serious, 2 patients) Bladder neoplasm (serious, 1 patient) Colon cancer (serious, 2 patients) Colorectal cancer (serious, 1 patient) Hepatic neoplasm (serious, 1 patient) Hepatobiliary neoplasm (serious, 1 patient) Adenocarcinoma lung (serious, 1 patient) Lung neoplasm malignant (serious, 1 patient) Lung squamous cell carcinoma stage unspecified (serious, 1 patient) Multiple myeloma (serious, 1 patient) Prostate cancer metastatic (serious, 1 patient) Uterine leiomyoma (serious, 1 patient) Anterior spinal artery syndrome (serious, 1 patient) Burning sensation (serious, 1 patient) Cerebral haematoma (serious, 1 patient) Coma (serious, 1 patient) Diabetic neuropathy (serious, 1 patient) Dizziness (serious, 4 patients) Dysarthria (serious, 1 patient) Embolic stroke (serious, 2 patients) Epilepsy (serious, 2 patients) Haemorrhagic stroke (serious, 1 patient) Intracranial haematoma (serious, 1 patient) Loss of consciousness (serious, 1 patient) Metabolic encephalopathy (serious, 1 patient) Myasthenia gravis (serious, 1 patient) Myasthenia gravis crisis (serious, 1 patient) Neuropathy peripheral (serious, 1 patient) Somnolence (serious, 2 patients) Trigeminal neuralgia (serious, 1 patient) Unresponsive to stimuli (serious, 1 patient) Uraemic encephalopathy (serious, 1 patient) Abnormal behaviour (serious, 1 patient) Alcohol abuse (serious, 1 patient) Anxiety (serious, 1 patient) Confusional state (serious, 2 patients) Depression suicidal (serious, 1 patient) Screaming (serious, 1 patient) Bladder tamponade (serious, 1 patient) Haematuria (serious, 1 patient) Nephropathy (serious, 1 patient) Polyuria (serious, 1 patient) Renal artery stenosis (serious, 1 patient) Renal failure acute (serious, 20 patients) Renal impairment (serious, 5 patients) Benign prostatic hyperplasia (serious, 2 patients) Menorrhagia (serious, 1 patient) Acute pulmonary oedema (serious, 7 patients) Acute respiratory distress syndrome (serious, 1 patient) Acute respiratory failure (serious, 2 patients) Asthma (serious, 1 patient) Atelectasis (serious, 1 patient) Bronchiectasis (serious, 1 patient) Chronic obstructive pulmonary disease (serious, 13 patients) Dyspnoea (serious, 20 patients) Pneumonitis (serious, 1 patient) Pneumothorax (serious, 1 patient) Productive cough (serious, 1 patient) Pulmonary artery thrombosis (serious, 1 patient) Respiratory failure (serious, 6 patients) Wheezing (serious, 1 patient) Hyperhidrosis (serious, 2 patients) Skin ulcer (serious, 1 patient) Skin ulcer haemorrhage (serious, 1 patient) Extremity necrosis (serious, 1 patient) Hypotension (serious, 24 patients) Peripheral arterial occlusive disease (serious, 4 patients) Peripheral ischaemia (serious, 1 patient) Disorder peripheral vascular (serious, 2 patients) Phlebitis (serious, 1 patient) Diarrhoea (below serious, 49 patients) Hyperkalaemia (below serious, 155 patients) Renal impairment (below serious, 47 patients) Cough (below serious, 59 patients) Hypotension (below serious, 117 patients) Sources: https://clinicaltrials.gov/ct2/show/NCT00894387
300 mg 1 times / day steady, oral Dose: 300 mg, 1 times / day Route: oral Route: steady Dose: 300 mg, 1 times / day Sources: https://clinicaltrials.gov/ct2/show/NCT00982033	unhealthy n = 25 Health Status: unhealthy Condition: Heart Failure and a Normal Ejection Fraction Population Size: 25 Sources: https://clinicaltrials.gov/ct2/show/NCT00982033	Other AEs: Thrush NOS... Other AEs: Thrush NOS (below serious, 1 patient) Sources: https://clinicaltrials.gov/ct2/show/NCT00982033
300 mg 1 times / day steady, oral (max) Dose: 300 mg, 1 times / day Route: oral Route: steady Dose: 300 mg, 1 times / day Sources: https://clinicaltrials.gov/ct2/show/NCT01417104	unhealthy n = 34 Health Status: unhealthy Condition: Atherosclerosis Population Size: 34 Sources: https://clinicaltrials.gov/ct2/show/NCT01417104	Other AEs: Hyperkalemia... Other AEs: Hyperkalemia (below serious, 1 patient) Sources: https://clinicaltrials.gov/ct2/show/NCT01417104

AEs

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1737	inhibitor 1767	inhibitor 1852 substrate 1217	inhibitor 1612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP1A2 1524 CYP2C8 911 CYP2C19 1478 CYP2E1 882 CYP3A4/5 278 BCRP 699 P-gp 1461	P-gp 1537 OATP1 3 OCT1 327 OCT3 80 MRP2 205 BCRP 561	CYP 76

Drug as perpetrator

Target	Modality	Activity
CYP1A2 1692	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/021985s000_ClinPharmR_P2.pdf Page: 12.0	no [Inhibition 100 uM]
CYP2C8 965	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/021985s000_ClinPharmR_P2.pdf Page: 12.0	no [Inhibition 100 uM]
CYP2E1 970	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/021985s000_ClinPharmR_P2.pdf Page: 12.0	no [Inhibition 100 uM]
CYP3A4/5 335	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/021985s000_ClinPharmR_P2.pdf Page: 12.0	no [Inhibition 100 uM]
CYP2C19 1553	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/021985s000_PharmR_P1.pdf Page: 46.0	no [Inhibition 200 uM]
CYP2C9 1819	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/021985s000_PharmR_P1.pdf Page: 46.0	no [Inhibition 200 uM]
CYP2D6 1891	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/021985s000_PharmR_P1.pdf Page: 46.0	no [Inhibition 200 uM]
CYP 147	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/021985s000_ClinPharmR_P4.pdf Page: 47.0	no
P-gp 1650	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/021985s000_ClinPharmR_P2.pdf Page: 21.0	no
BCRP 773	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/021985s000_ClinPharmR_P1.pdf Page: 30.0	yes

Drug as victim

Target	Modality	Activity	Clinical evidence
OATP1 3	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/021985s000_ClinPharmR_P1.pdf Page: 30, 57	inconclusive
CYP3A4 1737	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/021985s000_ClinPharmR_P1.pdf Page: 30.0	major	yes (co-administration study) Comment: itraconazole increased Cmax by 5-fold and AUC by 6-fold; ketaconazole increased Cmax a nd AUC by 2-fold; cyclosporine increased Cmax by 5-fold and AUC by 3-fold Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/021985s000_ClinPharmR_P1.pdf Page: 30.0
CYP2D6 1217	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/021985s000_ClinPharmR_P1.pdf Page: 30, 55, 56	minor
BCRP 561	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/021985s000_ClinPharmR_P1.pdf Page: 31.0	no
MRP2 205	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/021985s000_ClinPharmR_P1.pdf Page: 31.0	no
OCT1 327	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/021985s000_ClinPharmR_P1.pdf Page: 31, 57	no
OCT3 80	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/021985s000_ClinPharmR_P1.pdf Page: 31, 57	no
P-gp 1537	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/021985s000_ClinPharmR_P1.pdf Page: 31.0	yes	yes (co-administration study) Comment: from clinical pharmacology review pdf 4: ketaconazole increased Cmax by 81% and AUC by 76%; from product label: itraconazole increased Cmax by 5-fold and AUC by 6-fold; cyclosporine increased Cmax by 5-fold and AUC by 3-fold Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/021985s000_ClinPharmR_P1.pdf Page: 31.0

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1647	inhibitor 1626 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/021985s000_PharmR_P1.pdf Page: 46, 69

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:601027	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:601027
ChemicalBook	CB9966226	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB9966226
MolPort	MolPort-006-167-755	https://www.molport.com/shop/molecule-link/MolPort-006-167-755
MolPort	MolPort-028-956-725	https://www.molport.com/shop/molecule-link/MolPort-028-956-725
ZINC	ZINC000004393164	http://zinc15.docking.org/substances/ZINC000004393164
eMolecules	31229123	https://www.emolecules.com/cgi-bin/more?vid=31229123

PubMed

Title	Date	PubMed
Angiotensin II suppression in humans by the orally active renin inhibitor aliskiren (SPP100). Comparison with enalapril.	2002 Aug	12168611
Angiotensin II suppression in humans by the orally active renin inhibitor Aliskiren (SPP100): comparison with enalapril.	2002 Jan	11799102
Gateways to clinical trials.	2002 Oct	12500432
Gateways to Clinical Trials.	2002 Sep	12428432
Gateways to clinical trials.	2004 Jul-Aug	15349141
Pharmacokinetic interactions of the oral renin inhibitor aliskiren with lovastatin, atenolol, celecoxib and cimetidine.	2005 Nov	16300168
Aliskiren, a novel orally effective renin inhibitor, exhibits similar pharmacokinetics and pharmacodynamics in Japanese and Caucasian subjects.	2006 Dec	17118124
Renin inhibition with aliskiren: where are we now, and where are we going?	2006 Feb	16508564
[Trend of research and development of antihypertensive agents].	2006 Jul	16895229
Gateways to clinical trials.	2006 Jun	16845450
Direct renin inhibition with aliskiren in hypertension and target organ damage.	2006 Mar	17699210
Conformational changes in prorenin during renin inhibition in vitro and in vivo.	2006 Mar	16467656
[Antihypertensive drugs in clinical development].	2006 May	16819244
Gateways to clinical trials.	2006 Oct	17136234
Prorenin induces intracellular signaling in cardiomyocytes independently of angiotensin II.	2006 Oct	16940215
Potential side effects of renin inhibitors--mechanisms based on comparison with other renin-angiotensin blockers.	2006 Sep	16907653
The efficacy of aliskiren, a direct renin inhibitor, in the treatment of hypertension.	2007	17401313
Gateways to clinical trials.	2007 Apr	17520107
Angiotensin II reactivation and aldosterone escape phenomena in renin-angiotensin-aldosterone system blockade: is oral renin inhibition the solution?	2007 Apr	17376010
Absorption, distribution, metabolism, and elimination of the direct renin inhibitor aliskiren in healthy volunteers.	2007 Aug	17510248
Mechanisms of progression of chronic kidney disease.	2007 Dec	17647026
Pharmacokinetics, safety, and tolerability of the oral Renin inhibitor aliskiren in patients with hepatic impairment.	2007 Feb	17244770
Aliskiren reduces blood pressure and suppresses plasma renin activity in combination with a thiazide diuretic, an angiotensin-converting enzyme inhibitor, or an angiotensin receptor blocker.	2007 Feb	17159081
Renin inhibition with aliskiren provides additive antihypertensive efficacy when used in combination with hydrochlorothiazide.	2007 Jan	17143194
A new weapon against hypertension. Recently approved medication lowers blood pressure, reducing risks of heart failure, stroke, heart attack, aneurysm, and kidney failure.	2007 Jun	17654793
A new way to control blood pressure. Inactivating renin, which is made by the kidneys, may open the door to better blood pressure.	2007 May	17517983
Direct Renin inhibition with aliskiren in obese patients with arterial hypertension.	2007 May	17353513
A comparison of the tolerability of the direct renin inhibitor aliskiren and lisinopril in patients with severe hypertension.	2007 Oct	17541390
Renin inhibition: the holy grail of renin-angiotensin system blockade?	2007 Oct	17541389
Structural modification of the P2' position of 2,7-dialkyl-substituted 5(S)-amino-4(S)-hydroxy-8-phenyl-octanecarboxamides: the discovery of aliskiren, a potent nonpeptide human renin inhibitor active after once daily dosing in marmosets.	2007 Oct 4	17824680
The difficult conception, birth and delivery of a renin inhibitor: controversies around aliskiren.	2007 Sep	17762637

Patents

Sample Use Guides

In Vivo Use Guide

Starting dose: 150 mg once daily with a routine pattern with regard to meals. If blood pressure remains uncontrolled titrate up to 300 mg daily (2.1, 2.3) Majority of effect of given dose attained in 2 weeks

Route of Administration: Oral

In Vitro Use Guide

Aliskiren (0.1 or 10 uM) dose-dependently improved functions and increased both VEGF and stromal cell-derived factor-1α (SDF-1α) expression of EPCs from patients with T2DM or EPCs from healthy volunteers and treated with high glucose.

Substance Class	Chemical Created by `admin` on `Sat Dec 16 16:41:18 GMT 2023` Edited by `admin` on `Sat Dec 16 16:41:18 GMT 2023`
Record UNII	502FWN4Q32
Record Status	`Validated (UNII)`
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Name

Type

Language

ALISKIREN

Official Name

English

aliskiren [INN]

Common Name

English

ALISKIREN [USAN]

Common Name

English

Aliskiren [WHO-DD]

Common Name

English

ALISKIREN [EMA EPAR]

Common Name

English

SPP-100

Code

English

(2S,4S,5S,7S)-5-Amino-N-(2-carbamoyl-2-methylpropyl)-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropoxy)benzyl]-8-methylnonamide

Systematic Name

English

SPP100

Code

English

ALISKIREN [MI]

Common Name

English

ALISKIREN [HSDB]

Common Name

English

ALISKIREN [VANDF]

Common Name

English

Classification Tree Code System Code

NDF-RT

N0000175900