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Berotralstat

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16 US Patents, 4 US Exclusivities

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US Patents

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Chemistry

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Also known as: Berotralstat, 1809010-50-1, Bcx7353, Berotralstat [inn], Berotralstat [usan], Xza0kb1bdq

Molecular Formula

C₃₀H₂₆F₄N₆O

Molecular Weight

562.6 g/mol

InChI Key

UXNXMBYCBRBRFD-MUUNZHRXSA-N

FDA UNII

XZA0KB1BDQ

Berotralstat is a selective inhibitor of plasma kallikrein used in the prophylaxis of attacks of hereditary angioedema (HAE). It works by blocking the enzymatic activity of plasma kallikrein in releasing bradykinin, the major biologic peptide that promotes swelling and pain associated with attacks of HAE. Developed by BioCryst Pharmaceuticals, berotralstat is taken once-daily as oral capsules. Under the market name Orladeyo, berotralstat was approved by the FDA on December 3, 2020, as the first oral, once-daily therapy to prevent angioedema attacks of HAE in adults and pediatric patients 12 years and older. In clinical trials, berotralstat was shown to significantly reduce attack rates at 24 weeks compared to placebo, which was sustained through 48 weeks. Berotralstat is strictly used to prevent, but not treat, these attacks. Previous oral therapies used for prophylaxis of HAE attacks, such as androgens, were limited by undesirable adverse effects and several contraindications. In clinical trials, berotralstat displayed a fast onset of action, long duration of action, and acceptable tolerance in patients.

Berotralstat is a Plasma Kallikrein Inhibitor. The mechanism of action of berotralstat is as a Kallikrein Inhibitor, and Cytochrome P450 2D6 Inhibitor, and Cytochrome P450 3A4 Inhibitor, and P-Glycoprotein Inhibitor.

1 2D Structure

Berotralstat

2 Identification

2.1 Computed Descriptors

2.1.1 IUPAC Name

2-[3-(aminomethyl)phenyl]-N-[5-[(R)-(3-cyanophenyl)-(cyclopropylmethylamino)methyl]-2-fluorophenyl]-5-(trifluoromethyl)pyrazole-3-carboxamide

2.1.2 InChI

InChI=1S/C30H26F4N6O/c31-24-10-9-22(28(37-17-18-7-8-18)21-5-1-3-19(11-21)15-35)13-25(24)38-29(41)26-14-27(30(32,33)34)39-40(26)23-6-2-4-20(12-23)16-36/h1-6,9-14,18,28,37H,7-8,16-17,36H2,(H,38,41)/t28-/m1/s1

2.1.3 InChI Key

UXNXMBYCBRBRFD-MUUNZHRXSA-N

2.1.4 Canonical SMILES

C1CC1CNC(C2=CC(=C(C=C2)F)NC(=O)C3=CC(=NN3C4=CC=CC(=C4)CN)C(F)(F)F)C5=CC=CC(=C5)C#N

2.1.5 Isomeric SMILES

C1CC1CN[C@@H](C2=CC(=C(C=C2)F)NC(=O)C3=CC(=NN3C4=CC=CC(=C4)CN)C(F)(F)F)C5=CC=CC(=C5)C#N

2.2 Other Identifiers

2.2.1 UNII

XZA0KB1BDQ

2.3 Synonyms

2.3.1 MeSH Synonyms

1. 1-(3-(aminomethyl)phenyl)-n-(5-((r)-(3-cyanophenyl)((cyclopropylmethyl)amino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1h-pyrazole-5-carboxamide

2. 1h-pyrazole-5-carboxamide, 1-(3-(aminomethyl)phenyl)-n-(5-((r)-(3-cyanophenyl)((cyclopropylmethyl)

3. Bcx-7353

4. Bcx7353

5. Berotralstat

2.3.2 Depositor-Supplied Synonyms

1. Berotralstat

2. 1809010-50-1

3. Bcx7353

4. Berotralstat [inn]

5. Berotralstat [usan]

6. Xza0kb1bdq

7. Bcx-7353

8. Berotralstat (usan)

9. 2-[3-(aminomethyl)phenyl]-n-[5-[(r)-(3-cyanophenyl)-(cyclopropylmethylamino)methyl]-2-fluorophenyl]-5-(trifluoromethyl)pyrazole-3-carboxamide

10. 1-(3-(aminomethyl)phenyl)-n-(5-((r)-(3-cyanophenyl)((cyclopropylmethyl)amino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1h-pyrazole-5-carboxamide

11. 1h-pyrazole-5-carboxamide, 1-(3-(aminomethyl)phenyl)-n-(5-((r)-(3-cyanophenyl)((cyclopropylmethyl)amino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-

12. 1-[3-(aminomethyl)phenyl]-n-(5-{(r)-(3-cyanophenyl)[(cyclopropylmethyl)amino]methyl}-2-fluorophenyl)-3-(trifluoromethyl)-1h-pyrazole-5-carboxamide

13. Unii-xza0kb1bdq

14. Berotralstat [usan:inn]

15. Berotralstat [who-dd]

16. Schembl21974728

17. Gtpl11347

18. Dtxsid401336676

19. Ex-a5537

20. Who 10907

21. Hy-109127

22. Cs-0086757

23. D11673

24. (r)-1-(3-(aminomethyl)phenyl)-n-(5-((3-cyanophenyl)((cyclopropylmethyl)amino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1h-pyrazole-5-carboxamide

25. 0ri

26. 1-[3-(aminomethyl)phenyl]-n-(5-{(r)-[3-(aminomethyl)phenyl][(cyclopropylmethyl)amino]methyl}-2-fluorophenyl)-3-(trifluoromethyl)-1h-pyrazole-5-carboxamide

27. 1h-pyrazole-5-carboxamide, 1-(3-(aminomethyl)phenyl)-n-(5-((r)-(3-cyanophenyl)((cyclopropylmethyl)

2.4 Create Date

2019-03-16

3 Chemical and Physical Properties

Molecular Formula	C₃₀H₂₆F₄N₆O
Molecular Weight	562.6 g/mol
XLogP3	4.5
Hydrogen Bond Donor Count	3
Hydrogen Bond Acceptor Count	9
Rotatable Bond Count	9
Exact Mass	562.21042212 g/mol
Monoisotopic Mass	562.21042212 g/mol
Topological Polar Surface Area	109 Å²
Heavy Atom Count	41
Formal Charge	0
Complexity	938
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

Berotralstat is indicated for prophylaxis of attacks of hereditary angioedema (HAE) in adults and pediatric patients 12 years and older. It is not used for the treatment of acute HAE attacks.

Orladeyo is indicated for routine prevention of recurrent attacks of hereditary angioedema (HAE) in adult and adolescent patients aged 12 years and older.

5 Pharmacology and Biochemistry

5.1 Pharmacology

Berotralstat prevents angioedema attacks by inhibiting plasma kallikrein, thereby regulating excess bradykinin generation in patients with hereditary angioedema. It has a fast onset of action, long duration of action, and acceptable tolerance. Berotralstat inhibits plasma kallikrein in a concentration-dependent. In clinical trials, doses of berotralstat higher than 150 mg once daily led to QT Prolongation in a concentration-dependent manner.

5.2 MeSH Pharmacological Classification

Serine Proteinase Inhibitors

Exogenous or endogenous compounds which inhibit SERINE ENDOPEPTIDASES. (See all compounds classified as Serine Proteinase Inhibitors.)

5.3 FDA Pharmacological Classification

5.3.1 Active Moiety

BEROTRALSTAT

5.3.2 FDA UNII

XZA0KB1BDQ

5.3.3 Pharmacological Classes

Mechanisms of Action [MoA] - P-Glycoprotein Inhibitors

5.4 ATC Code

B06AC

B - Blood and blood forming organs

B06 - Other hematological agents

B06A - Other hematological agents

B06AC - Drugs used in hereditary angioedema

B06AC06 - Berotralstat

5.5 Absorption, Distribution and Excretion

Absorption

The steady-state of berotralstat is reached within 6 to 12 days following initial administration. After once-daily administration, the Cmax and AUC of berotralstat at steady-state is approximately five times that of the drug after a single dose. Following oral administration of berotralstat once-daily, the steady-state Cmax was 158 ng/mL (range: 110 to 234 ng/mL) at the dose of 150 mg and 97.8 ng/mL (range: 63 to 235 ng/mL) at the dose of 110 mg. The area under the curve over the dosing interval (AUCtau) was 2770 ng*hr/mL (range: 1880 to 3790 ng*hr/mL) and 1600 ng*hr/mL (range: 950 to 4170 ng*hr/mL) at the dose of 110 mg. The median Tmax is 2 hours in a fasted state and a high-fat meal delays the Tmax to 5 hours. The Tmax can range from 1 to 8 hours.

Route of Elimination

Following a single oral dose administration of 300 mg radiolabeled berotralstat, approximately 9% of the drug was excreted in the urine, where 1.8 to 4.7% of the total radiolabeled compound accounted for the unchanged parent drug. About 79% of the drug was excreted in feces.

Volume of Distribution

The blood to plasma ratio was approximately 0.92 following a single 300 mg dose administration of radiolabeled berotralstat.

Clearance

There is no information on the clearance rate.

5.6 Metabolism/Metabolites

Berotralstat is metabolized by CYP2D6 and CYP3A4. The metabolic pathway and the metabolites of berotralstat have not yet been characterized. Following a single oral dose administration of 300 mg radiolabeled berotralstat, about 34% of the total plasma radioactivity accounted for the unchanged drug while about eight detectable metabolites accounted for 1.8 to 7.8% of the total radioactivity.

5.7 Biological Half-Life

Following a single oral dose administration of 300 mg radiolabeled berotralstat, the median elimination half-life of berotralstat was approximately 93 hours, ranging from 39 to 152 hours.

5.8 Mechanism of Action

Hereditary angioedema (HAE) is a rare genetic disorder associated with severe swelling of the skin and upper airway. It is caused by mutations in the regulatory or coding regions of the gene that encodes C1 inhibitor (SERPING1), which result in either a deficiency (type I) or dysfunction (type II) of C1 inhibitor (C1 esterase inhibitor, C1-INH). C1 inhibitor is a serine protease inhibitor that normally regulates bradykinin production by covalently binding to and inactivating plasma kallikrein. Plasma kallikrein is a protease that cleaves high-molecular-weight-kininogen (HMWK) to generate cleaved HMWK (cHMWK). During HAE attacks, the levels of plasma kallikrein fall, leading to the cleavage of high-molecular-weight-kininogen and the release of bradykinin, a potent vasodilator that increases vascular permeability. Bradykinin plays a major role in promoting edema and pain associated with HAE. Patients with HAE cannot properly regulate plasma kallikrein activity due to the deficiency or dysfunction of a serum inhibitor of C1 inhibitor, leading to uncontrolled increases in plasma kallikrein activity and recurrent angioedema attacks. Berotralstat is a potent inhibitor of plasma kallikrein that works by binding to plasma kallikrein and blocking its proteolytic activity, thereby controlling excess bradykinin generation.

NDC API