OSILODROSTAT

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C13H10FN3
Molecular Weight	227.237
Optical Activity	UNSPECIFIED
Defined Stereocenters	1 / 1
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

[H][C@@]1(CCC2=CN=CN12)C3=CC=C(C=C3F)C#N

InChI

InChIKey=USUZGMWDZDXMDG-CYBMUJFWSA-N

InChI=1S/C13H10FN3/c14-12-5-9(6-15)1-3-11(12)13-4-2-10-7-16-8-17(10)13/h1,3,5,7-8,13H,2,4H2/t13-/m1/s1

HIDE SMILES / InChI

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/26542280
Curator's Comment: The description was created based on several sources, including https://clinicaltrials.gov/ct2/show/NCT02697734 | https://clinicaltrials.gov/ct2/show/NCT02468193 | https://clinicaltrials.gov/ct2/show/NCT02372084 | https://www.ncbi.nlm.nih.gov/pubmed/25981165

Osilodrostat (INN, USAN) (developmental code name LCI-699) is an orally active, non-steroidal corticosteroid biosynthesis inhibitor which is under development by Novartis for the treatment of Cushing's syndrome and pituitary ACTH hypersecretion (a specific subtype of Cushing's syndrome). Osilodrostat specifically acts as a potent and selective inhibitor of aldosterone synthase (CYP11B2) and at higher dosages of 11β-hydroxylase (CYP11B1). Osilodrostat decreases plasma and urinary aldosterone levels and rapidly corrects hypokalemia, in patients with primary aldosteronism and hypertension. At doses ≥1 mg o.d. Osilodrostat markedly increases 11-deoxycortisol plasma levels and blunts ACTH-stimulated cortisol release in ≈20% of patients, consistent with the inhibition of CYP11B1. In patients with resistant hypertension, Osilodrostat produces a non-significant reduction in blood pressure, possibly due to the increase in 11-deoxycortisol levels and the stimulation of the hypothalamic-pituitary-adrenal feedback axis. Because of the lack of selectivity, poor antihypertensive effect, and short half-life, the development of Osilodrostat as antihypertensive was halted. As of 2017, Osilodrostat is in phase III and phase II clinical trials for the treatment of pituitary ACTH hypersecretion and Cushing's syndrome, respectively.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Cytochrome P450 11B2 6 Target ID: CHEMBL2722 Sources: https://www.ncbi.nlm.nih.gov/pubmed/24422519	Inhibitor 8297		0.2 nM [IC50]
Cytochrome P450 11B1 9 Target ID: CHEMBL1908 Sources: https://www.ncbi.nlm.nih.gov/pubmed/24422519	Inhibitor 8297		2.9 nM [IC50]

Conditions

Condition	Modality	Highest Phase	Product
Cushing’s disease 13 Sources: https://clinicaltrials.gov/ct2/show/record/NCT02697734	Primary	Phase III 656	Unknown Approved Use Unknown
Adrenal adenoma 2 Sources: https://clinicaltrials.gov/ct2/show/NCT02468193	Primary	Phase II 1132	Unknown Approved Use Unknown
Adrenal carcinoma 2 Sources: https://clinicaltrials.gov/ct2/show/NCT02468193	Primary	Phase II 1132	Unknown Approved Use Unknown
Acth-independent macronodular adrenal hyperplasia 2 Sources: https://clinicaltrials.gov/ct2/show/NCT02468193	Primary	Phase II 1132	Unknown Approved Use Unknown
Primary pigmented nodular adrenocortical disease 2 Sources: https://clinicaltrials.gov/ct2/show/NCT02468193	Primary	Phase II 1132	Unknown Approved Use Unknown

C_max

Value	Dose	Co-administered	Analyte	Population
2340 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/25981165/	5 mg/kg 1 times / day multiple, oral dose: 5 mg/kg route of administration: Oral experiment type: MULTIPLE co-administered: PASIREOTIDE	PASIREOTIDE	OSILODROSTAT plasma	Rattus norvegicus population: HEALTHY age: ADULT sex: MALE food status: FED
2100 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/25981165/	5 mg/kg single, oral dose: 5 mg/kg route of administration: Oral experiment type: SINGLE co-administered: PASIREOTIDE	PASIREOTIDE	OSILODROSTAT plasma	Rattus norvegicus population: HEALTHY age: ADULT sex: MALE food status: FED
2170 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/25981165/	5 mg/kg single, oral dose: 5 mg/kg route of administration: Oral experiment type: SINGLE co-administered: PASIREOTIDE	PASIREOTIDE	OSILODROSTAT plasma	Rattus norvegicus population: HEALTHY age: ADULT sex: FEMALE food status: FED
634 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/25981165/	1.5 mg/kg single, oral dose: 1.5 mg/kg route of administration: Oral experiment type: SINGLE co-administered: PASIREOTIDE	PASIREOTIDE	OSILODROSTAT plasma	Rattus norvegicus population: HEALTHY age: ADULT sex: MALE food status: FED
999 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/25981165/	1.5 mg/kg 1 times / day multiple, oral dose: 1.5 mg/kg route of administration: Oral experiment type: MULTIPLE co-administered: PASIREOTIDE	PASIREOTIDE	OSILODROSTAT plasma	Rattus norvegicus population: HEALTHY age: ADULT sex: MALE food status: FED
608 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/25981165/	1.5 mg/kg single, oral dose: 1.5 mg/kg route of administration: Oral experiment type: SINGLE co-administered: PASIREOTIDE	PASIREOTIDE	OSILODROSTAT plasma	Rattus norvegicus population: HEALTHY age: ADULT sex: FEMALE food status: FED
6100 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/25981165/	20 mg/kg 1 times / day multiple, oral dose: 20 mg/kg route of administration: Oral experiment type: MULTIPLE co-administered: PASIREOTIDE	PASIREOTIDE	OSILODROSTAT plasma	Rattus norvegicus population: HEALTHY age: ADULT sex: MALE food status: FED
7200 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/25981165/	20 mg/kg single, oral dose: 20 mg/kg route of administration: Oral experiment type: SINGLE co-administered: PASIREOTIDE	PASIREOTIDE	OSILODROSTAT plasma	Rattus norvegicus population: HEALTHY age: ADULT sex: MALE food status: FED
2130 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/25981165/	5 mg/kg 1 times / day multiple, oral dose: 5 mg/kg route of administration: Oral experiment type: MULTIPLE co-administered: PASIREOTIDE	PASIREOTIDE	OSILODROSTAT plasma	Rattus norvegicus population: HEALTHY age: ADULT sex: FEMALE food status: FED
5490 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/25981165/	20 mg/kg single, oral dose: 20 mg/kg route of administration: Oral experiment type: SINGLE co-administered:		OSILODROSTAT plasma	Rattus norvegicus population: HEALTHY age: ADULT sex: FEMALE food status: FED
4930 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/25981165/	20 mg/kg 1 times / day multiple, oral dose: 20 mg/kg route of administration: Oral experiment type: MULTIPLE co-administered: PASIREOTIDE	PASIREOTIDE	OSILODROSTAT plasma	Rattus norvegicus population: HEALTHY age: ADULT sex: FEMALE food status: FED
306 ng/mL OTHER GOV https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/212801Orig1s000ClinPharmR.pdf	30 mg 2 times / day multiple, oral dose: 30 mg route of administration: Oral experiment type: MULTIPLE co-administered:		OSILODROSTAT unknown	Homo sapiens population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN
7.91 ng/mL OTHER GOV https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/212801Orig1s000ClinPharmR.pdf	2 mg single, oral dose: 2 mg route of administration: Oral experiment type: SINGLE co-administered:		OSILODROSTAT unknown	Homo sapiens population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN
617 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/25981165/	1.5 mg/kg 1 times / day multiple, oral dose: 1.5 mg/kg route of administration: Oral experiment type: MULTIPLE co-administered: PASIREOTIDE	PASIREOTIDE	OSILODROSTAT plasma	Rattus norvegicus population: HEALTHY age: UNKNOWN sex: FEMALE food status: FED

AUC

Value	Dose	Co-administered	Analyte	Population
11500 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/25981165/	5 mg/kg 1 times / day multiple, oral dose: 5 mg/kg route of administration: Oral experiment type: MULTIPLE co-administered: PASIREOTIDE	PASIREOTIDE	OSILODROSTAT plasma	Rattus norvegicus population: HEALTHY age: ADULT sex: MALE food status: FED
12700 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/25981165/	5 mg/kg single, oral dose: 5 mg/kg route of administration: Oral experiment type: SINGLE co-administered: PASIREOTIDE	PASIREOTIDE	OSILODROSTAT plasma	Rattus norvegicus population: HEALTHY age: ADULT sex: MALE food status: FED
15700 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/25981165/	5 mg/kg single, oral dose: 5 mg/kg route of administration: Oral experiment type: SINGLE co-administered: PASIREOTIDE	PASIREOTIDE	OSILODROSTAT plasma	Rattus norvegicus population: HEALTHY age: ADULT sex: FEMALE food status: FED
2450 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/25981165/	1.5 mg/kg single, oral dose: 1.5 mg/kg route of administration: Oral experiment type: SINGLE co-administered: PASIREOTIDE	PASIREOTIDE	OSILODROSTAT plasma	Rattus norvegicus population: HEALTHY age: ADULT sex: MALE food status: FED
2690 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/25981165/	1.5 mg/kg 1 times / day multiple, oral dose: 1.5 mg/kg route of administration: Oral experiment type: MULTIPLE co-administered: PASIREOTIDE	PASIREOTIDE	OSILODROSTAT plasma	Rattus norvegicus population: HEALTHY age: ADULT sex: MALE food status: FED
2730 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/25981165/	1.5 mg/kg single, oral dose: 1.5 mg/kg route of administration: Oral experiment type: SINGLE co-administered: PASIREOTIDE	PASIREOTIDE	OSILODROSTAT plasma	Rattus norvegicus population: HEALTHY age: ADULT sex: FEMALE food status: FED
50000 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/25981165/	20 mg/kg 1 times / day multiple, oral dose: 20 mg/kg route of administration: Oral experiment type: MULTIPLE co-administered: PASIREOTIDE	PASIREOTIDE	OSILODROSTAT plasma	Rattus norvegicus population: HEALTHY age: ADULT sex: MALE food status: FED
98000 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/25981165/	20 mg/kg single, oral dose: 20 mg/kg route of administration: Oral experiment type: SINGLE co-administered: PASIREOTIDE	PASIREOTIDE	OSILODROSTAT plasma	Rattus norvegicus population: HEALTHY age: ADULT sex: MALE food status: FED
13300 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/25981165/	5 mg/kg 1 times / day multiple, oral dose: 5 mg/kg route of administration: Oral experiment type: MULTIPLE co-administered: PASIREOTIDE	PASIREOTIDE	OSILODROSTAT plasma	Rattus norvegicus population: HEALTHY age: ADULT sex: FEMALE food status: FED
80400 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/25981165/	20 mg/kg single, oral dose: 20 mg/kg route of administration: Oral experiment type: SINGLE co-administered:		OSILODROSTAT plasma	Rattus norvegicus population: HEALTHY age: ADULT sex: FEMALE food status: FED
51600 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/25981165/	20 mg/kg 1 times / day multiple, oral dose: 20 mg/kg route of administration: Oral experiment type: MULTIPLE co-administered: PASIREOTIDE	PASIREOTIDE	OSILODROSTAT plasma	Rattus norvegicus population: HEALTHY age: ADULT sex: FEMALE food status: FED
1680 ng × h/mL OTHER GOV https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/212801Orig1s000ClinPharmR.pdf	30 mg 2 times / day multiple, oral dose: 30 mg route of administration: Oral experiment type: MULTIPLE co-administered:		OSILODROSTAT unknown	Homo sapiens population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN
38.6 ng × h/mL OTHER GOV https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/212801Orig1s000ClinPharmR.pdf	2 mg single, oral dose: 2 mg route of administration: Oral experiment type: SINGLE co-administered:		OSILODROSTAT unknown	Homo sapiens population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN
3010 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/25981165/	1.5 mg/kg 1 times / day multiple, oral dose: 1.5 mg/kg route of administration: Oral experiment type: MULTIPLE co-administered: PASIREOTIDE	PASIREOTIDE	OSILODROSTAT plasma	Rattus norvegicus population: HEALTHY age: UNKNOWN sex: FEMALE food status: FED

Doses

Dose	Population	Adverse events
7 mg 2 times / day steady, oral (typical) Recommended Dose: 7 mg, 2 times / day Route: oral Route: steady Dose: 7 mg, 2 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/212801s000lbl.pdf https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/212801Orig1s000MedR.pdf	unhealthy, 19-70 years n = 137 Health Status: unhealthy Condition: Cushing's disease Age Group: 19-70 years Sex: M+F Population Size: 137 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/212801s000lbl.pdf https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/212801Orig1s000MedR.pdf	Disc. AE: Hypocortisolism... AEs leading to discontinuation/dose reduction: Hypocortisolism Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/212801s000lbl.pdf https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/212801Orig1s000MedR.pdf
7 mg 2 times / day steady, oral (typical) Recommended Dose: 7 mg, 2 times / day Route: oral Route: steady Dose: 7 mg, 2 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/212801s000lbl.pdf https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/212801Orig1s000MedR.pdf	unhealthy, 19-70 years n = 137 Health Status: unhealthy Condition: Cushing's disease Age Group: 19-70 years Sex: M+F Population Size: 137 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/212801s000lbl.pdf https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/212801Orig1s000MedR.pdf	Disc. AE: Hypokalemia, Pituitary tumor NOS... Other AEs: Adrenal insufficiency, Fatigue... AEs leading to discontinuation/dose reduction: Hypokalemia (0.72%) Pituitary tumor NOS (5.8%) Other AEs: Adrenal insufficiency (43.1%) Fatigue (38.7%) Nausea (grade 1-2, 37.2%) Headache (30.7%) Edema (21.2%) Nasopharyngitis (19.7%) Vomiting (grade 1-2, 19%) Arthralgia (17.5%) Back pain (15.3%) Rash (15.3%) Diarrhea (grade 1-2, 14.6%) Blood corticotrophin increased (13.9%) Dizziness (13.9%) Abdominal pain (grade 1-2, 13.1%) Hypokalaemia (12.4%) Myalgia (12.4%) Decreased appetite (11.7%) Hormone level abnormal (11.7%) Hypotension (11.7%) Urinary tract infection (11.7%) Blood testosterone increased (10.9%) Pyrexia (10.9%) Anemia (10.2%) Cough (10.2%) Hypertension (10.2%) Influenza (10.2%) Adrenal insufficiency (43.1%) Fatigue (38.7%) Nausea (grade 1-2, 37.2%) Headache (30.7%) Edema (21.2%) Nasopharyngitis (19.7%) Vomiting (grade 1-2, 19%) Arthralgia (17.5%) Back pain (15.3%) Rash (15.3%) Diarrhea (grade 1-2, 14.6%) Blood corticotrophin increased (13.9%) Dizziness (13.9%) Abdominal pain (grade 1-2, 13.1%) Hypokalaemia (12.4%) Myalgia (12.4%) Decreased appetite (11.7%) Hormone level abnormal (11.7%) Hypotension (11.7%) Urinary tract infection (11.7%) Blood testosterone increased (10.9%) Pyrexia (10.9%) Anemia (10.2%) Cough (10.2%) Hypertension (10.2%) Influenza (10.2%) Hirsutism (9.5%) Acne (8.8%) Dyspepsia (8%) Insomnia (8%) Anxiety (7.3%) Depression (7.3%) Gastroenteritis (7.3%) Malaise (6.6%) Tachycardia (6.6%) Alopecia (5.8%) Transaminases increased (4.4%) QT interval prolonged (3.6%) Syncope (1.5%) Neutropenia (1.4%) Neutrophil count decreased (13.1%) ALT increased (grade 1, 4%) AST increased (grade 1, 4%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/212801s000lbl.pdf https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/212801Orig1s000MedR.pdf
5 mg 2 times / day steady, oral (median) Recommended Dose: 5 mg, 2 times / day Route: oral Route: steady Dose: 5 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/32730798/	unhealthy, 20-69 years n = 36 Health Status: unhealthy Condition: Cushing's disease Age Group: 20-69 years Sex: M+F Population Size: 36 Sources: https://pubmed.ncbi.nlm.nih.gov/32730798/	DLT: Rash, Visual impairment... Other AEs: Nausea, Anaemia... Dose limiting toxicities: Rash (3%) Visual impairment (3%) Headache (3%) Paresis cranial nerve (3%) Pituitary tumour benign (3%) Hypocortisolism (3%) Other AEs: Nausea (11%) Anaemia (8%) Arthralgia (8%) Headache (8%) Asthenia (6%) Blood corticotrophin increased (6%) Constipation (6%) Depression (6%) Dizziness (6%) Fatigue (6%) Hirsutism (6%) Nasopharyngitis (6%) Cough (3%) Insomnia (3%) Urinary tract infection (3%) Sources: https://pubmed.ncbi.nlm.nih.gov/32730798/
200 mg 1 times / day single, oral Highest studied dose Dose: 200 mg, 1 times / day Route: oral Route: single Dose: 200 mg, 1 times / day Sources: https://www.ema.europa.eu/en/documents/assessment-report/isturisa-epar-public-assessment-report_en.pdf	healthy n = 37 Health Status: healthy Sex: M Population Size: 37 Sources: https://www.ema.europa.eu/en/documents/assessment-report/isturisa-epar-public-assessment-report_en.pdf	Other AEs: Electrocardiogram QTc interval prolonged... Other AEs: Electrocardiogram QTc interval prolonged Sources: https://www.ema.europa.eu/en/documents/assessment-report/isturisa-epar-public-assessment-report_en.pdf
30 mg 2 times / day steady, oral (median) Highest studied dose Dose: 30 mg, 2 times / day Route: oral Route: steady Dose: 30 mg, 2 times / day Sources: https://www.ema.europa.eu/en/documents/assessment-report/isturisa-epar-public-assessment-report_en.pdf https://pubmed.ncbi.nlm.nih.gov/32730798/	unhealthy n = 5 Health Status: unhealthy Condition: Cushing's disease Sex: M+F Population Size: 5 Sources: https://www.ema.europa.eu/en/documents/assessment-report/isturisa-epar-public-assessment-report_en.pdf https://pubmed.ncbi.nlm.nih.gov/32730798/	Sources: https://www.ema.europa.eu/en/documents/assessment-report/isturisa-epar-public-assessment-report_en.pdf https://pubmed.ncbi.nlm.nih.gov/32730798/
30 mg 2 times / day steady, oral Recommended Dose: 30 mg, 2 times / day Route: oral Route: steady Dose: 30 mg, 2 times / day Sources: https://www.ema.europa.eu/en/documents/assessment-report/isturisa-epar-public-assessment-report_en.pdf	unhealthy n = 5 Health Status: unhealthy Sex: M+F Population Size: 5 Sources: https://www.ema.europa.eu/en/documents/assessment-report/isturisa-epar-public-assessment-report_en.pdf	Sources: https://www.ema.europa.eu/en/documents/assessment-report/isturisa-epar-public-assessment-report_en.pdf
150 mg single, oral Studied dose Dose: 150 mg Route: oral Route: single Dose: 150 mg Sources: https://www.ema.europa.eu/en/documents/assessment-report/isturisa-epar-public-assessment-report_en.pdf	healthy n = 86 Health Status: healthy Sex: M+F Population Size: 86 Sources: https://www.ema.europa.eu/en/documents/assessment-report/isturisa-epar-public-assessment-report_en.pdf	Other AEs: QT interval prolonged... Other AEs: QT interval prolonged (3.6%) Sources: https://www.ema.europa.eu/en/documents/assessment-report/isturisa-epar-public-assessment-report_en.pdf
20 mg 1 times / day steady, oral (median) Studied dose Dose: 20 mg, 1 times / day Route: oral Route: steady Dose: 20 mg, 1 times / day Sources: https://www.ema.europa.eu/en/documents/assessment-report/isturisa-epar-public-assessment-report_en.pdf	unhealthy n = 19 Health Status: unhealthy Condition: Cushing's disease Sex: M+F Population Size: 19 Sources: https://www.ema.europa.eu/en/documents/assessment-report/isturisa-epar-public-assessment-report_en.pdf	Other AEs: Headache, Adrenal insufficiency... Other AEs: Headache (grade 3-5, 5.3%) Adrenal insufficiency (grade 3-5, 5.3%) Hypertension (grade 3-5, 21.1%) Anaemia (grade 3-5, 5.3%) Depression (grade 3-5, 5.3%) Lipase increased (grade 3-5, 5.3%) Pituitary-dependent Cushing's syndrome (grade 3-5, 15.8%) Sources: https://www.ema.europa.eu/en/documents/assessment-report/isturisa-epar-public-assessment-report_en.pdf

AEs

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1737 inhibitor 1587 inducer 781	inhibitor 1767	substrate 1217 inhibitor 1852	inhibitor 1612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP11B1 10 CYP11B2 11 CYP1A2 1524 CYP2C19 1478 CYP2E1 882 CYP2B6 810 OCT2 647 MATE1 306 MATE2 263 CYP2A6 707 P-gp 1461 OAT1 599 OAT3 642 OATP1B1 788 OATP1B3 706 OCT1 512 BSEP 402 BCRP 699 MRP2 383 CYP2C8 911 CYP3A4/5 278 UGT1A1 204 UGT2B7 146	P-gp 1537 MRP 7 CYP2B6 664 UGT1A4 347 UGT2B7 389 UGT2B10 127	CYP1A2 701 CYP2B6 547

Drug as perpetrator

Target	Modality	Activity	Metabolite
CYP1A2 1692	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/212801Orig1s000ClinPharmR.pdf#page=10 Page: 10.0	moderate [Ki 0.175 uM]
CYP2C19 1553	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/212801Orig1s000ClinPharmR.pdf#page=10 Page: 10.0	moderate [Ki 1 uM]
OAT3 644	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/212801Orig1s000PharmR.pdf#page=40 Page: 40.0	no [IC50 3.23 uM]	LXB168 2
OAT3 644	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/212801Orig1s000PharmR.pdf#page=40 Page: 40.0	no [IC50 45 uM]
OAT1 603	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/212801Orig1s000PharmR.pdf#page=40 Page: 40.0	no [IC50 >100 uM]
OCT1 543	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/212801Orig1s000PharmR.pdf#page=40 Page: 40.0	no [IC50 >100 uM]
BCRP 773	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/212801Orig1s000PharmR.pdf#page=40 Page: 40.0	no
BCRP 773	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/212801Orig1s000PharmR.pdf#page=40 Page: 40.0	no	LXB168 2
BSEP 403	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/212801Orig1s000PharmR.pdf#page=40 Page: 40.0	no
CYP1A2 1692	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/212801Orig1s000PharmR.pdf#page=41 Page: 41.0	no	LXB168 2
CYP2A6 739	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/212801Orig1s000PharmR.pdf#page=41 Page: 41.0	no
CYP2A6 739	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/212801Orig1s000PharmR.pdf#page=41 Page: 41.0	no	LXB168 2
CYP2C19 1553	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/212801Orig1s000PharmR.pdf#page=41 Page: 41.0	no	LXB168 2
CYP2C8 965	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/212801Orig1s000PharmR.pdf#page=41 Page: 41.0	no	LXB168 2
CYP2C9 1819	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/212801Orig1s000PharmR.pdf#page=41 Page: 41.0	no	LXB168 2
CYP2D6 1891	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/212801Orig1s000PharmR.pdf#page=41 Page: 41.0	no	LXB168 2
CYP3A4/5 335	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/212801Orig1s000PharmR.pdf#page=41 Page: 41.0	no	LXB168 2
MATE2 263	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/212801Orig1s000PharmR.pdf#page=40 Page: 40.0	no	LXB168 2
MRP2 475	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/212801Orig1s000PharmR.pdf#page=40 Page: 40.0	no
MRP2 475	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/212801Orig1s000PharmR.pdf#page=40 Page: 40.0	no	LXB168 2
OATP1B1 803	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/212801Orig1s000PharmR.pdf#page=40 Page: 40.0	no
OATP1B1 803	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/212801Orig1s000PharmR.pdf#page=40 Page: 40.0	no	LXB168 2
OATP1B3 715	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/212801Orig1s000PharmR.pdf#page=40 Page: 40.0	no
OATP1B3 715	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/212801Orig1s000PharmR.pdf#page=40 Page: 40.0	no	LXB168 2
OCT1 543	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/212801Orig1s000PharmR.pdf#page=40 Page: 40.0	no	LXB168 2
OCT2 648	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/212801Orig1s000PharmR.pdf#page=40 Page: 40.0	no	LXB168 2
P-gp 1650	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/212801Orig1s000PharmR.pdf#page=40 Page: 40.0	no
UGT2B7 157	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/212801Orig1s000PharmR.pdf#page=41 Page: 41.0	no
UGT2B7 157	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/212801Orig1s000PharmR.pdf#page=41 Page: 41.0	no	LXB168 2
CYP2D6 1891	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/212801Orig1s000ClinPharmR.pdf#page=10 Page: 10.0	weak [Ki 2 uM]
CYP2C9 1819	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/212801Orig1s000ClinPharmR.pdf#page=10 Page: 10.0	weak [Ki 20 uM]
CYP3A4 1925	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/212801Orig1s000ClinPharmR.pdf#page=10 Page: 10.0	weak [Ki 3.25 uM]
CYP11B2 12	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/212801Orig1s000ClinPharmR.pdf#page=8 Page: 8.0	yes [IC50 0.7 uM]
UGT1A1 254	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/212801Orig1s000PharmR.pdf#page=41 Page: 41.0	yes [IC50 0.7 uM]	LXB168 2
OAT1 603	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/212801Orig1s000PharmR.pdf#page=40 Page: 40.0	yes [IC50 19.9 uM]	LXB168 2
UGT1A1 254	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/212801Orig1s000PharmR.pdf#page=41 Page: 41.0	yes [IC50 30 uM]
MATE2 263	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/212801Orig1s000ClinPharmR.pdf#page=40 Page: 40.0	yes [IC50 37.7 uM]
MATE1 308	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/212801Orig1s000ClinPharmR.pdf#page=40 Page: 40.0	yes [IC50 5.57 uM]
MATE1 308	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/212801Orig1s000PharmR.pdf#page=40 Page: 40.0	yes [IC50 67.6 uM]	LXB168 2
OCT2 648	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/212801Orig1s000ClinPharmR.pdf#page=40 Page: 40.0	yes [IC50 8.59 uM]
BSEP 403	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/212801Orig1s000PharmR.pdf#page=40 Page: 40.0	yes [IC50 >50 uM]	LXB168 2
P-gp 1650	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/212801Orig1s000PharmR.pdf#page=40 Page: 40.0	yes [IC50 >50 uM]	LXB168 2
CYP2E1 970	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/212801Orig1s000ClinPharmR.pdf#page=10 Page: 10.0	yes [Ki 0.482 uM]
CYP2B6 1001	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/212801Orig1s000ClinPharmR.pdf#page=10 Page: 10.0	yes [Ki 10 uM]
CYP2B6 1001	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/212801Orig1s000ClinPharmR.pdf#page=51 Page: 51.0	yes [Ki 225 uM]	LXB168 2
CYP3A4 1925	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/212801Orig1s000ClinPharmR.pdf#page=51 Page: 51.0	yes [Ki 86.3 uM]	LXB168 2
CYP11B1 10	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/212801Orig1s000ClinPharmR.pdf#page=8 Page: 8.0	yes
CYP1A2 1692	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/212801Orig1s000ClinPharmR.pdf#page=10 Page: 10.0	yes
CYP2B6 1001	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/212801Orig1s000ClinPharmR.pdf#page=10 Page: 10.0	yes
CYP3A4 1925	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/212801Orig1s000ClinPharmR.pdf#page=10 Page: 10.0	yes

Drug as victim

Target	Modality	Activity	Clinical evidence
MRP 7	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/212801Orig1s000ClinPharmR.pdf#page=9 Page: 9.0	no
P-gp 1537	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/212801Orig1s000ClinPharmR.pdf#page=9 Page: 9.0	no
CYP2D6 1217	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/212801Orig1s000ClinPharmR.pdf#page=9 Page: 9.0	yes [Km 30.4 uM]	unlikely Comment: Due to the available high Km,u values (~30 μM) for CYP3A4, CYP2B6 and CYP2D6, these enzymes are not likely saturated at clinically relevant doses since Cmax is about 0.88 μM following multiple dose administration of 30 mg osilodrostat twice daily Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/212801Orig1s000ClinPharmR.pdf#page=9 Page: 9.0
CYP2B6 664	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/212801Orig1s000ClinPharmR.pdf#page=9 Page: 9.0	yes [Km 36.1 uM]	unlikely Comment: Due to the available high Km,u values (~30 μM) for CYP3A4, CYP2B6 and CYP2D6, these enzymes are not likely saturated at clinically relevant doses since Cmax is about 0.88 μM following multiple dose administration of 30 mg osilodrostat twice daily Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/212801Orig1s000ClinPharmR.pdf#page=9 Page: 9.0
CYP3A4 1737	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/212801Orig1s000ClinPharmR.pdf#page=9 Page: 9.0	yes [Km 36.1 uM]	unlikely Comment: Due to the available high Km,u values (~30 μM) for CYP3A4, CYP2B6 and CYP2D6, these enzymes are not likely saturated at clinically relevant doses since Cmax is about 0.88 μM following multiple dose administration of 30 mg osilodrostat twice daily Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/212801Orig1s000ClinPharmR.pdf#page=9 Page: 9.0
UGT1A4 347	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/212801Orig1s000ClinPharmR.pdf#page=9 Page: 9.0	yes
UGT2B10 127	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/212801Orig1s000ClinPharmR.pdf#page=9 Page: 9.0	yes
UGT2B7 389	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/212801Orig1s000ClinPharmR.pdf#page=9 Page: 9.0	yes

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1647	inhibitor 1626 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/212801Orig1s000PharmR.pdf#page=31 Page: 31.0

Sourcing

Vendor/Aggregator	ID	URL
AA Blocks	AA00H1GZ	https://www.aablocks.com/goods/Goods/detail?id=AA00H1GZ
AbMole Bioscience	M5233	http://www.abmole.com/products/lci699.html
Achemtek	0102-014347	http://www.achemtek.com/928134-65-0
Ambinter	Amb24088170	http://www.ambinter.com/reference/24088170
Aurum Pharmatech LLC	Z-3271	http://www.Aurumpharmatech.com/Product/ProductDetails/Z_3271
BLD Pharm	BD00936116	http://www.bldpharm.com/products/P000906684.html
Chem Scene	CS-6896	http://www.chemscene.com/928134-65-0.html
Chemspace	CSSB00102420042	https://chem-space.com/CSSB00102420042
Excenen	EX-A1397	http://www.excenen.com/searchresultlist.php?id=928134-65-0
Hairui	OSXM016	http://www.hairuichem.com/en/product/928134-65-0.html
Lab Network	LN01345822	https://labnetwork.com/frontend-app/p/#!/moleculedetails/LN01345822
MedChem Express	HY-16276	https://www.medchemexpress.com/Osilodrostat.html
Smolecule	S548884	http://www.smolecule.com/products/s548884
THE BioTek	bt-288287	https://www.thebiotek.com/product/inhibitors/bt-288287
eNovation Chemicals	D548085	http://www.enovationchem.com/productDetails.asp?productID=D548085
eNovation Chemicals	Y0975639	https://www.enovationchem.com/ProductDetails.asp?ProductID=Y0975639

PubMed

Title	Date	PubMed
Efficacy and safety of LCI699 for hypertension: a meta-analysis of randomized controlled trials and systematic review.	2015	25683946

Patents

Sample Use Guides

In Vivo Use Guide

1, 5, 10, or 20 mg/day for 48-weeks

Route of Administration: Oral

In Vitro Use Guide

For in vitro measurement of aldosterone activity, human adrenocortical carcinoma NCI-H295R cells are seeded in NBS 96-well plates at a density of 25,000 cells/well in 100 μl of a growth medium containing DMEM/F12 supplemented with 10% FCS, 2.5% Nuserum, 1 μg ITS/ml, and 1x antibiotic/antimycotic. The medium is changed after culturing for 3 days at 37 C under an atmosphere of 5% CO2/95% air. On the following day, cells are rinsed with 100 μl of DMEM/F12 and incubated with 100 μl of treatment medium containing 1 µM Ang II and a compound 7n (Osilodrostat) at different concentrations in quadruplicate wells at 37C for 24 hr. At the end of incubation, 50 μl of medium is withdrawn from each well for measurement of aldosterone production by an RIA using mouse anti-aldosterone monoclonal antibodies.

Name

Type

Language

OSILODROSTAT

Official Name

English

Osilodrostat [WHO-DD]

Common Name

English

LCI-699-NX

Code

English

BENZONITRILE, 4-((5R)-6,7-DIHYDRO-5H-PYRROLO(1,2-C)IMIDAZOL-5-YL)-3-FLUORO-

Systematic Name

English

OSILODROSTAT [USAN]

Common Name

English

osilodrostat [INN]

Common Name

English

LCI699

Common Name

English

4-((5R)-6,7-DIHYDRO-5H-PYRROLO(1,2-C)IMIDAZOL-5-YL)-3-FLUORO-BENZONITRILE

Systematic Name

English

(+)-OSILODROSTAT

Common Name

English

OSILODROSTAT [MI]

Common Name

English

LCI699-NX

Code

English

LCI-699

Common Name

English

Classification Tree Code System Code

NCI_THESAURUS

C471