ambroxol   

GtoPdb Ligand ID: 10692

ambroxol is an approved drug
Compound class: Synthetic organic
Comment: Ambroxol stimulates the synthesis and release of surfactant in the respiratory tract and acts as a mucoactive/expectorant drug. This action appears to be associated with ambroxol's regulation of glucosylceramide levels, via modulation of non-lysosomal glucosylceramidase (GCase) beta 2 (GBA2; Q9HCG7). Ambroxol is reported to act as a small molecule chaperone for GCase proteins that can increase the stability and function of mutant and wild-type GCases in in vitro and in vivo models [4-5,7-8,15], and in clinical trial subjects [12,16]. Ambroxol binds to nascent GCase proteins (at the enzyme active site) within the endoplasmic reticulum, and this action facilitates transport to the lysosome [1,4]. The acidic lysosomal environment provokes ambroxol dissassociation, leaving the enzyme free to function normally.
2D Structure
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Physico-chemical Properties
Hydrogen bond acceptors 3
Hydrogen bond donors 3
Rotatable bonds 3
Topological polar surface area 58.28
Molecular weight 375.98
XLogP 2.9
No. Lipinski's rules broken 0
SMILES / InChI / InChIKey
Canonical SMILES OC1CCC(CC1)NCc1cc(Br)cc(c1N)Br
Isomeric SMILES OC1CCC(CC1)NCc1cc(Br)cc(c1N)Br
InChI InChI=1S/C13H18Br2N2O/c14-9-5-8(13(16)12(15)6-9)7-17-10-1-3-11(18)4-2-10/h5-6,10-11,17-18H,1-4,7,16H2
InChI Key JBDGDEWWOUBZPM-UHFFFAOYSA-N
References
1. Bendikov-Bar I, Maor G, Filocamo M, Horowitz M. (2013)
Ambroxol as a pharmacological chaperone for mutant glucocerebrosidase.
Blood Cells Mol. Dis., 50 (2): 141-5. [PMID:23158495]
2. Bouscary A, Quessada C, Mosbach A, Callizot N, Spedding M, Loeffler JP, Henriques A. (2019)
Ambroxol Hydrochloride Improves Motor Functions and Extends Survival in a Mouse Model of Familial Amyotrophic Lateral Sclerosis.
Front Pharmacol, 10: 883. [PMID:31447678]
3. Cazan D, Klimek L, Sperl A, Plomer M, Kölsch S. (2018)
Safety of ambroxol in the treatment of airway diseases in adult patients.
Expert Opin Drug Saf, 17 (12): 1211-1224. [PMID:30372367]
4. Luan Z, Li L, Higaki K, Nanba E, Suzuki Y, Ohno K. (2013)
The chaperone activity and toxicity of ambroxol on Gaucher cells and normal mice.
Brain Dev., 35 (4): 317-22. [PMID:22682976]
5. Maegawa GH, Tropak MB, Buttner JD, Rigat BA, Fuller M, Pandit D, Tang L, Kornhaber GJ, Hamuro Y, Clarke JT et al.. (2009)
Identification and characterization of ambroxol as an enzyme enhancement agent for Gaucher disease.
J. Biol. Chem., 284 (35): 23502-16. [PMID:19578116]
6. Malerba M, Ragnoli B. (2008)
Ambroxol in the 21st century: pharmacological and clinical update.
Expert Opin Drug Metab Toxicol, 4 (8): 1119-29. [PMID:18680446]
7. McNeill A, Magalhaes J, Shen C, Chau KY, Hughes D, Mehta A, Foltynie T, Cooper JM, Abramov AY, Gegg M et al.. (2014)
Ambroxol improves lysosomal biochemistry in glucocerebrosidase mutation-linked Parkinson disease cells.
Brain, 137 (Pt 5): 1481-95. [PMID:24574503]
8. Migdalska-Richards A, Daly L, Bezard E, Schapira AH. (2016)
Ambroxol effects in glucocerebrosidase and α-synuclein transgenic mice.
Ann. Neurol., 80 (5): 766-775. [PMID:27859541]
9. Migdalska-Richards A, Ko WKD, Li Q, Bezard E, Schapira AHV. (2017)
Oral ambroxol increases brain glucocerebrosidase activity in a nonhuman primate.
Synapse, 71 (7). [PMID:28295625]
10. Migdalska-Richards A, Schapira AH. (2016)
The relationship between glucocerebrosidase mutations and Parkinson disease.
J. Neurochem., 139 Suppl 1: 77-90. [PMID:26860875]
11. Mullin S, Smith L, Lee K, D'Souza G, Woodgate P, Elflein J, Hällqvist J, Toffoli M, Streeter A, Hosking J et al.. (2020)
Ambroxol for the Treatment of Patients With Parkinson Disease With and Without Glucocerebrosidase Gene Mutations: A Nonrandomized, Noncontrolled Trial.
JAMA Neurol, 77 (4): 427-434. [PMID:31930374]
12. Narita A, Shirai K, Itamura S, Matsuda A, Ishihara A, Matsushita K, Fukuda C, Kubota N, Takayama R, Shigematsu H et al.. (2016)
Ambroxol chaperone therapy for neuronopathic Gaucher disease: A pilot study.
Ann Clin Transl Neurol, 3 (3): 200-15. [PMID:27042680]
13. Sidransky E, Nalls MA, Aasly JO, Aharon-Peretz J, Annesi G, Barbosa ER, Bar-Shira A, Berg D, Bras J, Brice A et al.. (2009)
Multicenter analysis of glucocerebrosidase mutations in Parkinson's disease.
N. Engl. J. Med., 361 (17): 1651-61. [PMID:19846850]
14. Silveira CRA, MacKinley J, Coleman K, Li Z, Finger E, Bartha R, Morrow SA, Wells J, Borrie M, Tirona RG et al.. (2019)
Ambroxol as a novel disease-modifying treatment for Parkinson's disease dementia: protocol for a single-centre, randomized, double-blind, placebo-controlled trial.
BMC Neurol, 19 (1): 20. [PMID:30738426]
15. Yang SY, Beavan M, Chau KY, Taanman JW, Schapira AHV. (2017)
A Human Neural Crest Stem Cell-Derived Dopaminergic Neuronal Model Recapitulates Biochemical Abnormalities in GBA1 Mutation Carriers.
Stem Cell Reports, 8 (3): 728-742. [PMID:28216145]
16. Zimran A, Altarescu G, Elstein D. (2013)
Pilot study using ambroxol as a pharmacological chaperone in type 1 Gaucher disease.
Blood Cells Mol. Dis., 50 (2): 134-7. [PMID:23085429]