Berotralstat

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C30H26F4N6O
Molecular Weight	562.5607
Optical Activity	( + )
Defined Stereocenters	1 / 1
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

SMILES

NCC1=CC(=CC=C1)N2N=C(C=C2C(=O)NC3=CC(=CC=C3F)[C@H](NCC4CC4)C5=CC=CC(=C5)C#N)C(F)(F)F

InChI

InChIKey=UXNXMBYCBRBRFD-MUUNZHRXSA-N

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

HIDE SMILES / InChI

Molecular Formula	C30H26F4N6O
Molecular Weight	562.5607
Charge	0
Count	MOL RATIO 1 MOL RATIO (average)

Stereochemistry	ABSOLUTE
Additional Stereochemistry	No
Defined Stereocenters	1 / 1
E/Z Centers	0
Optical Activity	UNSPECIFIED

Description

Berotralstat (ORLADEYO™; BCX7353) is an orally administered kallikrein inhibitor, which has been developed by BioCryst Pharmaceuticals for hereditary angioedema (HAE). The inhibition of kallikrein by berotralstat decreases the production of bradykinin, which prevents the localised tissue oedema that occurs during attacks of HAE. Berotralstat has been approved in the USA, and subsequently in Japan, for prophylaxis to prevent attacks of HAE in adults and paediatric patients aged 12 years or older.

CNS Activity

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Plasma kallikrein 9	Inhibitor 8,456		44.0 nM [Ki]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Hereditary angioedema 6	Preventive		Approved 8,548	ORLADEYO

C_max

Value	Dose	Analyte	Population
97.8 ng/mL	110 mg 1 times / day steady-state, oral	BEROTRALSTAT plasma	Homo sapiens
158 ng/mL	150 mg 1 times / day steady-state, oral	BEROTRALSTAT plasma	Homo sapiens
45.5 ng/mL	150 mg single, oral	BEROTRALSTAT plasma	Homo sapiens
45.9 ng/mL	150 mg single, oral	BEROTRALSTAT plasma	Homo sapiens
80.5 ng/mL	150 mg single, oral	BEROTRALSTAT plasma	Homo sapiens
57.9 ng/mL	150 mg single, oral	BEROTRALSTAT plasma	Homo sapiens
68.3 ng/mL	150 mg single, oral	BEROTRALSTAT plasma	Homo sapiens
89 ng/mL	200 mg single, oral	BEROTRALSTAT plasma	Homo sapiens
130 ng/mL	200 mg single, oral	BEROTRALSTAT plasma	Homo sapiens

AUC

Value	Dose	Analyte	Population
1600 ng × h/mL	110 mg 1 times / day steady-state, oral	BEROTRALSTAT plasma	Homo sapiens
2770 ng × h/mL	150 mg 1 times / day steady-state, oral	BEROTRALSTAT plasma	Homo sapiens
907 ng × h/L	150 mg single, oral	BEROTRALSTAT plasma	Homo sapiens
945 ng × h/L	150 mg single, oral	BEROTRALSTAT plasma	Homo sapiens
1620 ng × h/L	150 mg single, oral	BEROTRALSTAT plasma	Homo sapiens
850 ng × h/L	150 mg single, oral	BEROTRALSTAT plasma	Homo sapiens
1250 ng × h/L	150 mg single, oral	BEROTRALSTAT plasma	Homo sapiens
2063 ng × h/L	200 mg single, oral	BEROTRALSTAT plasma	Homo sapiens
2252 ng × h/L	200 mg single, oral	BEROTRALSTAT plasma	Homo sapiens

T_1/2

Value	Dose	Co-administered	Analyte	Population
93 h	single, oral		BEROTRALSTAT plasma	Homo sapiens

F_unbound

Value	Dose	Co-administered	Analyte	Population
1%	300 mg single, oral		BEROTRALSTAT plasma	Homo sapiens

Doses

Show entries

Dose	Population	Adverse events
150 mg 1 times / day multiple, oral Recommended	unhealthy, ADOLESCENT	Disc. AE: Alanine aminotransferase increased, Aspartate aminotransferase increased...
150 mg 1 times / day multiple, oral Recommended	unhealthy, ADOLESCENT,ADULT	Disc. AE: Laboratory abnormality or Adverse event...
110 mg 1 times / day multiple, oral Studied dose	unhealthy, ADOLESCENT\|ADULT	Disc. AE: Laoratory abnormality or Adverse event, Gastrointestinal abdominal adverse event...
110 mg 1 times / day multiple, oral Studied dose	unhealthy, ADOLESCENT\|ADULT	Disc. AE: Alanine aminotransferase increased, Aspartate aminotransferase increased...

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AEs

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AE	Significance	Dose	Population
Abdominal pain upper	0.8% Disc. AE	150 mg 1 times / day multiple, oral Recommended	unhealthy, ADOLESCENT
Aspartate aminotransferase increased	0.8% Disc. AE	150 mg 1 times / day multiple, oral Recommended	unhealthy, ADOLESCENT
Diarrhea	0.8% Disc. AE	150 mg 1 times / day multiple, oral Recommended	unhealthy, ADOLESCENT
Hepatic enzyme test increased	0.8% Disc. AE	150 mg 1 times / day multiple, oral Recommended	unhealthy, ADOLESCENT
Liver function test abnormal	0.8% Disc. AE	150 mg 1 times / day multiple, oral Recommended	unhealthy, ADOLESCENT

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Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1,929 inhibitor 2,238	inhibitor 2,416	inhibitor 2,486 substrate 1,378	inhibitor 2,195

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP2C19 2,042 P-gp 1,725 BCRP 899 OATP2B1 157 OCT2 770 MATE1 409 OAT1 717 MATE2-K 75 OATP1B3 952 MRP2 498 OATP1A2 43 OATP1B1 1,068 OAT3 740	BCRP 687 OAT3 385 OATP1B3 430 OATP1B1 497 P-gp 2,035 MATE1 180 OAT1 391 MATE2-K 32 OCT2 430

Drug as perpetrator

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Target	Modality	Activity	Clinical evidence
CYP2D6 2,525	inhibitor 4,001	moderate [IC50 2.3 uM]	yes (co-administration study)
CYP3A4 2,613	inhibitor 4,001	moderate [IC50 2.5 uM]	yes (co-administration study)
BCRP 974	inhibitor 4,001	no [IC50 12 uM]	yes (co-administration study)
MRP2 619	inhibitor 4,001	no [IC50 >100 uM]
OAT1 722	inhibitor 4,001	no [IC50 >30 uM]

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Drug as victim

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Target	Modality	Activity
MATE1 180	substrate 3,987	no
MATE2-K 32	substrate 3,987	no
OAT1 391	substrate 3,987	no
OAT3 385	substrate 3,987	no
OATP1B1 497	substrate 3,987	no

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Tox targets

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Target	Modality	Activity	Metabolite	Clinical evidence
hERG 2,240	inhibitor 2,215

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PubMed

Title	Date	PubMed
No data available in table

Patents

Sample Use Guides

In Vivo Use Guide

Recommended Dosage: One capsule (150 mg) taken orally once daily with food.

Route of Administration: Oral

In Vitro Use Guide

In vitro data demonstrate that BCX7353 is a potent inhibitor of purified plasma kallikrein, with a Ki of 44nM (Study BR-7353-001). BCX7353 has also been shown to have acceptable selectivity for plasma kallikrein over other related serine proteases, with an IC50 of 0.88 nM against plasma kallikrein and IC50 ranging from 3967nM (against plasmin) to >50,000nM against other related serine proteases. BCX7353 was also shown to suppress HK/PKK-dependent BK production on human endothelial cells, with an EC50 of 5.56nM.

Substance Class	Chemical
Record UNII	XZA0KB1BDQ
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

BCX-7353

Preferred Name

English

Berotralstat

Official Name

English

Berotralstat [USAN]

Common Name

English

Berotralstat [INN]

Common Name

English

1H-Pyrazole-5-carboxamide, 1-[3-(aminomethyl)phenyl]-N-[5-[(R)-(3-cyanophenyl)[(cyclopropylmethyl)amino]methyl]-2-fluorophenyl]-3-(trifluoromethyl)-

Systematic Name

English

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Code System

Code

Type

Description

RXCUI

2467540

PRIMARY

CAS

1809010-50-1

PRIMARY

FDA UNII

XZA0KB1BDQ

PRIMARY

EPA CompTox

DTXSID401336676

PRIMARY

SMS_ID

300000005926

PRIMARY

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Related Record

Type

Details


					8YE5ABM3A9

Berotralstat, (S)-

ENANTIOMER -> ENANTIOMER

Amount:


					S8TIM42R2W

BRADYKININ

TARGET->INHIBITOR OF EXPRESSION

Amount:


					X4L6L7841X

PLASMA KALLIKREIN

TARGET -> INHIBITOR

Qualification:

Ki

Amount:


					76UB6O122H

ATP-BINDING CASSETTE SUB-FAMILY G MEMBER 2

TRANSPORTER -> SUBSTRATE


					88SH1NBL2B

Berotralstat hydrochloride

SALT/SOLVATE -> PARENT

Amount:

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Related Record

Type

Details


					XZA0KB1BDQ

Berotralstat

ACTIVE MOIETY

Amount:

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Name	Property Type	Amount	Parameters
Tmax	PHARMACOKINETIC	5 hours [1 to 8] (average)	FED CONDITION ORAL ADMINISTRATION

Biological Half-life	PHARMACOKINETIC	93 hours [39 to 152] (average)	ORAL ADMINISTRATION

blood to plasma ratio	PHARMACOKINETIC	0.92 hours (average)	SINGLE DOSE 300 mg (average)

SMILES

InChI

CNS Activity

Approval Year

Targets

Conditions

Cmax

AUC

T1/2

Funbound

Doses

AEs

Overview

OverviewOther

Drug as perpetrator​

Drug as victim

Tox targets

PubMed

Patents

Sample Use Guides

C_max

T_1/2

F_unbound

Drug as perpetrator