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Synopsis

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Chemistry

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Also known as: 928134-65-0, Isturisa, Lci-699, (+)-osilodrostat, Lci699-nx, Osilodrostat free base

Molecular Formula

C₁₃H₁₀FN₃

Molecular Weight

227.24 g/mol

InChI Key

USUZGMWDZDXMDG-CYBMUJFWSA-N

FDA UNII

5YL4IQ1078

Osilodrostat is an orally bioavailable inhibitor of both steroid 11beta-hydroxylase (cytochrome P450 (CYP) 11B1) and aldosterone synthase (CYP11B2; steroid 18-hydroxylase), with potential anti-adrenal activity and ability to treat Cushing disease (CD). Upon administration, osilodrostat binds to and inhibits the activity of CYP11B1, the enzyme that catalyzes the final step of cortisol synthesis from the precursor 11-deoxycortisol, and CYP11B2, the enzyme that catalyzes aldosterone synthesis from corticosterone and 11-deoxycorticosterone in the adrenal gland. The inhibition of CYP11B1 prevents the production of excess cortisol, thereby decreasing and normalizing the levels of cortisol. CD is most often caused by an adrenocorticotropic hormone (ACTH)-secreting pituitary tumor.

Osilodrostat is a Cortisol Synthesis Inhibitor. The mechanism of action of osilodrostat is as a Cytochrome P450 11B1 Inhibitor, and Cytochrome P450 1A2 Inhibitor, and Cytochrome P450 2C19 Inhibitor, and Cytochrome P450 2D6 Inhibitor, and Cytochrome P450 3A4 Inhibitor, and Cytochrome P450 3A5 Inhibitor.

1 2D Structure

Osilodrostat

2 Identification

2.1 Computed Descriptors

2.1.1 IUPAC Name

4-[(5R)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl]-3-fluorobenzonitrile

2.1.2 InChI

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

2.1.3 InChI Key

USUZGMWDZDXMDG-CYBMUJFWSA-N

2.1.4 Canonical SMILES

C1CC2=CN=CN2C1C3=C(C=C(C=C3)C#N)F

2.1.5 Isomeric SMILES

C1CC2=CN=CN2[C@H]1C3=C(C=C(C=C3)C#N)F

2.2 Other Identifiers

2.2.1 UNII

5YL4IQ1078

2.3 Synonyms

2.3.1 MeSH Synonyms

1. (+)-osilodrostat

2. 4-((5r)-6,7-dihydro-5h-pyrrolo(1,2-c)imidazol-5-yl)-3-fluoro-benzonitrile

3. Benzonitrile, 4-((5r)-6,7-dihydro-5h-pyrrolo(1,2-c)imidazol-5-yl)-3-fluoro-

4. Isturisa

2.3.2 Depositor-Supplied Synonyms

1. 928134-65-0

2. Isturisa

3. Lci-699

4. (+)-osilodrostat

5. Lci699-nx

6. Osilodrostat Free Base

7. Lci-699-nx

8. Chembl3099695

9. 5yl4iq1078

10. (r)-4-(6,7-dihydro-5h-pyrrolo[1,2-c]imidazol-5-yl)-3-fluorobenzonitrile

11. 4-[(5r)-6,7-dihydro-5h-pyrrolo[1,2-c]imidazol-5-yl]-3-fluorobenzonitrile

12. 4-[(5r)-6,7-dihydro-5h-pyrrolo[1,2-c]imidazol-5-yl]-3-fluorobenzo Nitrile

13. 4-((5r)-6,7-dihydro-5h-pyrrolo(1,2-c)imidazol-5-yl)-3-fluoro-benzonitrile

14. 4-[(4r,5r)-6,7-dihydro-5h-pyrrolo[1,2-c]imidazol-5-yl]-3-fluorobenzonitrile

15. Benzonitrile, 4-((5r)-6,7-dihydro-5h-pyrrolo(1,2-c)imidazol-5-yl)-3-fluoro-

16. Osilodrostat [usan:inn]

17. Lci 699

18. Osilodrostat [mi]

19. Osilodrostat (usan/inn)

20. Osilodrostat [inn]

21. Osilodrostat [usan]

22. Osilodrostat [who-dd]

23. Unii-5yl4iq1078

24. Gtpl8310

25. Schembl12460772

26. Dtxsid40156570

27. Ex-a1397

28. Bdbm50444549

29. S7456

30. Zinc72318114

31. Ccg-266774

32. Cs-6896

33. Db11837

34. 1304733-26-3

35. Ac-32907

36. Bs-17881

37. Hy-16276

38. D11061

39. A909743

40. Q27088216

2.4 Create Date

2009-08-10

3 Chemical and Physical Properties

Molecular Formula	C₁₃H₁₀FN₃
Molecular Weight	227.24 g/mol
XLogP3	1.9
Hydrogen Bond Donor Count	0
Hydrogen Bond Acceptor Count	3
Rotatable Bond Count	1
Exact Mass	227.08587549 g/mol
Monoisotopic Mass	227.08587549 g/mol
Topological Polar Surface Area	41.6 Å²
Heavy Atom Count	17
Formal Charge	0
Complexity	337
Isotope Atom Count	0
Defined Atom Stereocenter Count	1
Undefined Atom Stereocenter Count	0
Defined Bond Stereocenter Count	0
Undefined Bond Stereocenter Count	0
Covalently Bonded Unit Count	1

4 Drug and Medication Information

4.1 Drug Indication

Osilodrostat is indicated for the treatment of adult patients with Cushing's disease for whom pituitary surgery is not an option or has not been curative.

FDA Label

Isturisa is indicated for the treatment of endogenous Cushings syndrome in adults.

5 Pharmacology and Biochemistry

5.1 Pharmacology

Osilodrostat lowers endogenous cortisol levels by inhibiting the enzyme that catalyzes the final step in cortisol synthesis. As endogenous cortisol levels function as a surrogate marker for drug effect, 24-hour urine free cortisol levels should be assessed 1-2x weekly during the initial titration stage and every 1-2 months thereafter to ensure cortisol levels remain physiologically appropriate. Osilodrostat is highly metabolized and requires dose adjustments in patient with hepatic dysfunction. Osilodrostat can cause a dose-dependent prolongation of the QTc interval and should be used with caution in patients with a higher baseline risk (e.g. concomitant QTc-prolonging medications, electrolyte abnormalities). Prior to beginning therapy, patients should have a baseline ECG and any electrolyte abnormalities (especially hypokalemia and/or hypomagnesemia) should be remedied. As osilodrostat halts cortisol synthesis at its final stage, its use can result in the accumulation of cortisol precursors, aldosterone precursors, and androgens. The accumulation of the cortisol precursor 11-deoxycorticosterone can activate mineralocorticoid receptors which may lead to hypokalemia, edema, or hypertension. Patients should be monitored for these symptoms as they are evidence of elevated 11-deoxycorticosterone levels, and for symptoms such as hirustism, acne, and hypertrichosis which may be suggestive of excessive circulating androgen levels.

5.2 FDA Pharmacological Classification

5.2.1 Active Moiety

OSILODROSTAT

5.2.2 FDA UNII

5YL4IQ1078

5.2.3 Pharmacological Classes

Mechanisms of Action [MoA] - Cytochrome P450 3A5 Inhibitors

5.3 ATC Code

H02CA02

H - Systemic hormonal preparations, excl. sex hormones and insulins

H02 - Corticosteroids for systemic use

H02C - Antiadrenal preparations

H02CA - Anticorticosteroids

H02CA02 - Osilodrostat

5.4 Absorption, Distribution and Excretion

Absorption

The oral absorption of osilodrostat is rapid, with a T_max of approximately 1 hour, and assumed to be essentially complete. Exposure (i.e. AUC and C_max) increases slightly more than dose-proportionately over the standard dosing range. Coadministration of osilodrostat with food does not affect its pharmacokinetics to a clinically significant extent. Age and gender do not affect pharmacokinetics, but bioavailability and total exposure is higher (though not clinically significant) in patients of Asian descent. Exposure to osilodrostat is greater in patients with moderate-severe hepatic impairment - prescribing information recommends a starting dose of 1mg twice daily in patients with moderate hepatic impairment (Child-Pugh B) and a starting dose of 1mg each evening in patients with severe hepatic impairment (Child-Pugh C).

Route of Elimination

Following oral administration of radiolabeled osilodrostat, 90.6% of the radioactivity was eliminated in the urine with only 1.58% in the feces. Only 5.2% of the administered dose was eliminated in the urine as unchanged parent drug, suggesting that metabolism followed by urinary elimination is osildrostat's primary means of clearance.

Volume of Distribution

The median apparent volume of distribution of osilodrostat is 100 L.

Clearance

Data regarding the oral clearance of osilodrostat are not currently available.

5.5 Metabolism/Metabolites

Osilodrostat is extensively metabolized - approximately 80% of an orally administered dose is excreted as metabolites, and this is the predominant means of drug clearance. The most abundant metabolites in plasma are M35.4 (di-oxygenated osilodrostat), M16.5, and M24.9 at 51%, 9%, and 7% of the administered dose, respectively. The M34.5 and M24.9 metabolites have longer half-lives than the parent drug which may lead to accumulation with twice-daily dosing. Of the thirteen metabolites observed in the urine, the most abundant are M16.5 (osilodrostat glucuronide), M22 (a glucuronide conjugate of M34.5), and M24.9 at 17%, 13%, and 11% of the administered dose, respectively. The M34.5 metabolite accounts for less than 1% of the dose excreted in urine, but its glucuronide conjugate (M22) accounts for approximately 13%. The biotransformation of osilodrostat is mediated by multiple cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT) enzymes, though no single enzyme appears to contribute >25% to the total clearance. Of the total clearance, approximately 26% is CYP-mediated, 19% is UGT-mediated, and 50% is mediated by other enzymes. The formation of M34.5, the major metabolite of osilodrostat, is likely non-CYP-mediated. The formation of osilodrostat glucuronide (M16.5), its major urinary metabolite, is catalyzed by UGT1A4, UGT2B7, and UGT2B10. _In vitro_ data suggest that none of the metabolites contribute to the therapeutic efficacy of osilodrostat, but the M34.5 metabolite has been implicated in the inhibition and/or induction of multiple enzymes and transporters.

5.6 Biological Half-Life

The elimination half-life of osilodrostat is approximately 4 hours.

5.7 Mechanism of Action

Cushings syndrome is an endocrine disorder resulting from chronic and excessive exposure to glucocorticoids, the symptoms of which may include thinning of the skin and hair, weight gain, muscle weakness, and osteoporosis, as well a constellation of psychiatric, cardiovascular, and immunological deficiencies. Cushings syndrome is most commonly precipitated by exogenous treatment with supraphysiological doses of glucocorticoids such as those found in nasal sprays, skin creams, and inhalers. Cushings disease - another less common cause of Cushings syndrome - is generally the result of increased endogenous cortisol exposure due to excessive secretion of adrenocroticotrophic hormone (ACTH) from a pituitary adenoma. Osilodrostat is an inhibitor of 11-hydroxylase (CYP11B1) and, to a lesser extent, aldosterone synthase (CYP11B2). The CYP11B1 enzyme is responsible for catalyzing the final step of cortisol synthesis - by inhibiting this enzyme, osilodrostat helps to normalize endogenous cortisol levels and alleviate symptoms of Cushings disease.

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