berotralstat   Click here for help

GtoPdb Ligand ID: 11347

Synonyms: BCX-7353 | BCX7353 | Orladeyo®
Approved drug PDB Ligand
berotralstat is an approved drug (FDA (2020), EMA (2021))
Compound class: Synthetic organic
Comment: Berotralstat (BCX7353) is an orally bioavailable inhibitor of plasma kallikrein, a proteinase that is encoded by the KLKB1 gene in humans [4]. Plasma kallikrein cleaves Lys-Arg and Arg-Ser bonds in (human) kininogen to release bradykinin. Inhibition of this activity is exploited to reduce bradykinin levels in human disease where abnormally elevated bradykinin induces pathologic vascular permeability and swelling, as seen in patients with hereditary angioedema (HAE; caused by loss of C1 inhibitor SERPING1 expression).
The 'flat' structure of berotralstat with no specified stereochemistry is claimed as compound 52h in Biocryst Pharmaceuticals' patent WO2015134998A1 [3].
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2D Structure
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Physico-chemical Properties
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Hydrogen bond acceptors 6
Hydrogen bond donors 3
Rotatable bonds 11
Topological polar surface area 108.24
Molecular weight 562.21
XLogP 4.86
No. Lipinski's rules broken 0
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Canonical SMILES NCc1cccc(c1)n1nc(cc1C(=O)Nc1cc(ccc1F)[C@@H](c1cccc(c1)C#N)NCC1CC1)C(F)(F)F
Isomeric SMILES NCc1cccc(c1)n1nc(cc1C(=O)Nc1cc(ccc1F)[C@@H](c1cccc(c1)C#N)NCC1CC1)C(F)(F)F
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
1. Aygören-Pürsün E, Bygum A, Grivcheva-Panovska V, Magerl M, Graff J, Steiner UC, Fain O, Huissoon A, Kinaciyan T, Farkas H et al.. (2018)
Oral Plasma Kallikrein Inhibitor for Prophylaxis in Hereditary Angioedema.
N Engl J Med, 379 (4): 352-362. [PMID:30044938]
2. EMA. 
EU/3/18/2028 berotralstat orphan designation.
Accessed on 08/12/2020. Modified on 08/12/2020.,
3. Kotian PL, Babu YS, Wu M, Chintareddy VR, Kumar VS, Zhang W. (2015)
Human plasma kallikrein inhibitors.
Patent number: WO2015134998A1. Assignee: Biocryst Pharmaceuticals. Priority date: 07/03/2014. Publication date: 11/09/2015.
4. Kotian PL, Wu M, Vadlakonda S, Chintareddy V, Lu P, Juarez L, Kellogg-Yelder D, Chen X, Muppa S, Chambers-Wilson R et al.. (2021)
Berotralstat (BCX7353): Structure-Guided Design of a Potent, Selective, and Oral Plasma Kallikrein Inhibitor to Prevent Attacks of Hereditary Angioedema (HAE).
J Med Chem, 64 (17): 12453-12468. [PMID:34436898]
5. Lee A. (2021)
Berotralstat: First Approval.
Drugs, 81 (3): 405-409. [PMID:33646555]
6. Ohsawa I, Honda D, Suzuki Y, Fukuda T, Kohga K, Morita E, Moriwaki S, Ishikawa O, Sasaki Y, Tago M et al.. (2021)
Oral berotralstat for the prophylaxis of hereditary angioedema attacks in patients in Japan: A phase 3 randomized trial.
Allergy, 76 (6): 1789-1799. [PMID:33247955]
7. Zuraw B, Lumry WR, Johnston DT, Aygören-Pürsün E, Banerji A, Bernstein JA, Christiansen SC, Jacobs JS, Sitz KV, Gower RG et al.. (2021)
Oral once-daily berotralstat for the prevention of hereditary angioedema attacks: A randomized, double-blind, placebo-controlled phase 3 trial.
J Allergy Clin Immunol, 148 (1): 164-172.e9. [PMID:33098856]