Future
Editorial Special Focus Issue: Rare Diseases
Medicinal Chemistry
For reprint orders, please contact [email protected]
Glucocerebrosidase inhibitors: future drugs for the treatment of Gaucher disease? “
The application of inhibitor molecules as intracellular activators of the enzyme in lysosome is a paradigm inherent to pharmacological chaperone therapy approach.
”
Keywords: Gaucher disease • glucocerebrosidase • inhibitors • lysosomal storage disorders • pharmacological chaperone • rare diseaseww
Gaucher disease (GD) is the most widespread lysosomal storage disorder (LSD) caused by a defective activity of β-glucocerebrosidase (GCase; EC 3.2.1.45) [1,2] , the lysosomal β-glucosidase enzyme that catalyzes the hydrolysis of glucosylceramide (GlcCer) into glucose and ceramide. A deficit in enzyme activity results in the accumulation of the glycolipid substrate in macrophages and triggers severe symptoms, such as hepatosplenomegaly, anemia, bone lesions and respiratory failure, and, in more acute cases, affect CNS [3] . Three clinical types of GD have been described based upon the absence (type 1) or the presence and severity (types 2 and 3) of neurological impact [2] . However, recent studies have described the presence of peripheral and central neurological effects in type 1 GD patients [4] ; this has led to the suggestion that GD may be more appropriately described as a continuum of clinical m anifestations rather than distinct subtypes [5] . Therapeutic treatments for GD Current treatment approaches for GD comprise the replacement of the defective enzyme with recombinant enzyme, or the inhibition of the enzyme responsible for GlcCer production [6] . Although these treatments can reduce the symptoms significantly and improve the quality life of type 1 Gaucher patients, they are not reported to be effective on types 2 and 3. Pharmacological chaperone (PC) therapy (PCT) consists of the functional rescuing of misfolded proteins by specific ligands, which, after binding, enhance biosynthesis
10.4155/FMC.14.41 © 2014 Future Science Ltd
and/or prevent/correct premature degradation [7] . PCT either alone or in combination with enzyme replacement, has been proposed as an alternative therapy for GD and other LSDs [8–10] . PCT is based on the use of smallmolecule competitive GCase inhibitors to specifically bind and potentially stabilize catalytically competent GCase variants in the endoplasmic reticulum, assisting mutant protein folding and facilitating the trafficking to the lysosome, where the chaperone–enzyme complex dissociates and the stored GlcCer would be enzymatically degraded. There is an inherent contradiction associated with PCT; it relies on the lysosomal enhancement of enzyme activity with a molecule that inhibits it. In practice, this is resolved by using the molecule at subinhibitory concentrations that are still able to stabilize the protein. Conceptually, rescuing mutated proteins using subinhibitory concentrations of PCs is advantageous when compared with the established therapies. This strategy is based on small molecules, and therefore has the potential for oral bioavailability and blood–brain barrier permeability, and specifically targets the endogenous mutated enzyme to promote a selective activity enhancement. Inhibitors as pharmaceutical chaperones The majority of PC candidates have been selected from GCase competitive inhibitors, which bind to the enzyme active center and reduce the substrate lysosomal degradation. A large variety of molecules have been
Future Med. Chem. (2014) 6(9), 975–978
Ana Trapero Laboratory of Medicinal Chemistry, Department of Biomedicinal Chemistry, Institut de Química Avançada de Catalunya (IQAC–CSIC), Jordi Girona 18-26, 08034 Barcelona, Spain
Amadeu Llebaria Author for correspondence: Laboratory of Medicinal Chemistry, Department of Biomedicinal Chemistry, Institut de Química Avançada de Catalunya (IQAC–CSIC), Jordi Girona 18-26, 08034 Barcelona, Spain Tel.: +34 934 006 108 Fax: +34 932 045 904 amadeu.llebaria@ cid.csic.es
part of
ISSN 1756-8919
975
Editorial Trapero & Llebaria tested as GCase PCs including carbohydrate mimetics (amino cyclitols and iminosugars) or noncarbohydrate compounds discovered by high-throughput screening [8,11–12] . The success of a PC depends significantly on the structure and biophysical properties that determine specificity, affinity and reversibility of protein binding, in addition to membrane permeability and subcellular targeting.
“
Pharmacological chaperone therapy either alone or in combination with enzyme replacement, has been proposed as an alternative therapy for Gaucher disease and other lysosomal storage disorders.
”
PCT is an attractive approach for enhancing enzyme activity and is rapidly evolving towards therapeutic uses. However, several concerns have been raised on its clinical translation. First, most of the PCs reported are active site-directed and, thus, potential inhibitors of target enzymes. In addition, chaperones are usually effective in some missense mutations mainly located in specific enzyme domains, having low or no activity in some others, and are thus potentially appropriate for only a limited number of patients. These problems can be addressed by the identification of novel and allosteric noninhibitory chaperones that stabilize mutant enzymes and promote trafficking out of the endoplasmic reticulum. Allosteric compounds do not bind to the orthosteric substrate binding site, but to an alternatively located site whereby they can potentiate or inhibit the activity of the protein on its natural ligand. Recently, GCase activator compounds binding to allosteric sites and devoid of inhibitory effects have been described [13] , providing the basis for the development of a novel class of PC for GD treatment, which would probably resolve some of the problems associated with active site inhibitors and, thereby, greatly simplify the administration and dosing necessary with maximize enzyme activity. Allosteric ligands for other types of proteins have been successfully developed to drugs, and research is particularly active in G protein-coupled receptors for CNS diseases [14] . The approaches to allosteric molecules for G protein-coupled receptors could be adapted to rare diseases to increase the discovery of new hit compounds. Another problem to therapeutic application of PCs may be the achievement of insufficient enhancement of residual enzyme activity. Most of the PCs reported to date for type 1 GD have similar effects increasing two- to three-fold the residual cellular activity of N370S GCase independently of their affinity for the mutant protein [11] . Treatment with Plicera (Amicus Therapeutics, NJ, USA), the leading clinical candidate for PCT for GD, increased enzymatic activity for all patients enrolled in
976
Future Med. Chem. (2014) 6(9)
a Phase II trial showing a positive safety profile. However, Plicera development was stopped owing to lack of efficacy demonstrating significant clinical improvements in only one patient out of 18 [15] . This result could indicate that the increase of the residual GCase activity achieved with Plicera is too low for therapeutic effectiveness. Although these results were unsatisfactory, the GD patient who demonstrated a clinically significant improvement exemplifies the first proof-of-concept in humans for a PCT treatment of GD. In addition to Plicera, a clinical trial was recently initiated to test the activity of a known drug as a PC for GD. This is a repurposing of ambroxol, a systemically active mucolytic drug that showed positive results in initial in vitro studies [16] ; however, this study has suspended participant recruitment [17] . Another limitation of most of the described compounds as PCs is related to the apparently low potency in GCase activity enhancement in intact cells. Most of the PC candidates are effective in cells at concentrations much higher than those required for isolated enzyme inhibition, although some exceptions exist. The reasons for this are not clear, but can be related to low membrane permeability, unsuitable cell distribution or protein targeting, or a high metabolism, among others. The requirement of high concentrations is a strong limitation on PC’s drug development and is not desirable, owing to toxicity and target selectivity issues, a fact that seriously affects the in vivo tests of the compounds, where dose adjustment is crucial. Moreover, the range of concentrations where a molecule results in enzyme activation before reaching inhibition should be expanded, to ensure that there is a safe therapeutic window. This must allow for a dosing scheme guaranteeing that effective drug concentrations are reached in vivo and also that the target enzyme is not inhibited after proper enzyme folding and trafficking to the lysosome. Furthermore, ADME and the administration mode can affect the time course of the molecule and its activity and it seems reasonable to consider these factors early in the discovery phase.
“
The failure in clinical development of pharmacological chaperones for Gaucher disease and the low number of molecules arriving at clinical phases reflects the difficulties in finding therapies for this disease...
”
In vivo studies evaluating the potential usefulness of a PC for GD are hampered by the difficulties in the development of viable and efficient animal models suitable for testing the PC candidate molecules [18,19] . Most of the GD animal models are obtained by altering the expression or the activity of GCase, and therefore are not
future science group
Glucocerebrosidase inhibitors & Gaucher disease
appropriate to test the enzyme recovery. This represents an important drawback for the preclinical development of PCT candidates, which is being currently addressed [20] and will probably require future research efforts. Future outlook in the design of GCase inhibitors The failure in clinical development of PCs for GD and the low number of molecules arriving at clinical phases reflects the difficulties in finding therapies for this disease and also the special characteristics of enzyme activity enhancement by PCT. Learning the lessons from the past, one can conclude that the evolution of GCase inhibitors hit compounds towards PC leads requires a careful molecule selection and optimization of the strategies in the discovery phase. In addition, the activity profiling assays should be modified to reflect more closely the situation found in GD cells. Currently, most of the activity optimization is being performed testing molecules in wild-type enzyme assays, and measuring the enzyme inhibition in front of unnatural substrates or performing biophysical tests, very often using recombinant purified protein. This approach can be used for a very preliminary screening but is probably too far from the cell and tissue environments with high concentrations of GlcCer and mutated protein found in vivo. This can References 1
Futerman AH, van Meer G. The cell biology of lysosomal storage disorders. Nat. Rev. Mol. Cell Biol. 5(7), 554–565 (2004).
2
Grabowski GA. Phenotype, diagnosis, and treatment of Gaucher’s disease. Lancet 372(9645), 1263–1271 (2008).
3
Zhao H, Grabowski GA. Gaucher disease: perspectives on a prototype lysosomal disease. Cell. Mol. Life Sci. 59(4), 694–707 (2002).
4
Chérin, P, Rose C, de Roux-Serratrice C et al. The neurological manifestations of Gaucher disease type 1: the French Observatoire on Gaucher disease (FROG). J. Inherit. Metab. Dis. 33(4), 331–338 (2010).
lead to misleading outputs and false-positive molecules that will probably fail at a later stage. Finally, in vivo assays with animal models suitable for PCT must be validated to better reproduce the patient disease and treatment situation. The application of inhibitor molecules as intra cellular activators of the enzyme in lysosome is a paradigm inherent to PCT approach. However, the fact that several inhibitors are progressing in PCT clinical trials for LSDs indicates that this does not constitute an unsurmountable problem. Probably the lack of success in GD can be attributed, at least in part, to an inadequate selection and optimization of the lead candidates. This opens prospects for future research to define new molecules having improved properties and to establish assays to better select PCT candidates for this disease. Financial & competing interests disclosure This work was supported by the Spanish MICINN (CTQ201129549-C02-01) and ‘Generalitat de Catalunya’ (grant 2009SGR-1072). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript. 10
Suzuki Y, Ogawa S, Sakakibara Y. Chaperone therapy for neuronopathic lysosomal diseases: competitive inhibitors as chemical chaperones for enhancement of mutant enzyme activities. Perspect. Med. Chem. 3, 7–19 (2009).
11
Trapero A, Llebaria A. Glucocerebrosidase inhibitors for the treatment of Gaucher disease. Future Med. Chem. 5(5), 573–590 (2013).
12
Benito JM, García Fernández JM, Ortiz Mellet C. Pharmacological chaperone therapy for Gaucher disease: a patent review. Expert Opin. Ther. Pat. 21(6), 885–903 (2011).
13
Patnaik S, Zheng W, Choi JH et al. Discovery, structure-activity relationship, and biological evaluation of noninhibitory small molecule chaperones of glucocerebrosidase. J. Med. Chem. 55(12), 5734–5748 (2012).
5
Sidransky E. Gaucher disease: complexity in a ‘simple’ disorder. Mol. Genet. Metab. 83(1–2), 6–15 (2004).
6
Bennett LL, Mohan D. Gaucher disease and its treatment options. Ann. Pharmacother. 47(9), 1182–1193 (2013).
14
7
Leidenheimer NJ, Ryder KG. Pharmacological chaperoning: a primer on mechanism and pharmacology. Pharmacol. Res. 83C, 10–19 (2014).
Conn PJ, Christopoulos A, Lindsley CW. Allosteric modulators of GPCRs: a novel approach for the treatment of CNS disorders. Nat. Rev. Drug Discov. 8(1), 41–54 (2009).
15
Amicus Therapeutics announces preliminary results of Phase II study with plicera for Gaucher disease. http://ir.amicustherapeutics.com/ReleaseDetail. cfm?ReleaseID=413437
16
Maegawa GH, Tropak MB, Buttner JD et al. Identification and characterization of ambroxol as an enzyme enhancement agent for Gaucher disease. J. Biol. Chem. 284(35), 23502–23516 (2009).
8
Boyd RE, Lee G, Rybczynski P et al. Pharmacological chaperones as therapeutics for lysosomal storage diseases. J. Med. Chem. 56(7), 2705–2725 (2013).
9
Parenti G. Treating lysosomal storage diseases with pharmacological chaperones: from concept to clinics. EMBO Mol. Med. 1(5), 268–279 (2009).
future science group
Editorial
www.future-science.com
977
Editorial Trapero & Llebaria
978
17
Clinical Trial of Ambroxol in Patients With Type I Gaucher Disease. http://clinicaltrials.gov/ct2/show/NCT01463215
19
Farfel-Becker T, Vitner EB, Futerman AH. Animal models for Gaucher disease research. Dis. Model. Mech. 4(6), 746–752 (2011).
18
Vaquer G, Rivière F, Mavris M et al. Animal models for metabolic, neuromuscular and ophthalmological rare diseases. Nat. Rev. Drug Discov. 12(4), 287–305 (2013).
20
Sanders A, Hemmelgarn H, Melrose HL, Hein L, Fuller M, Clarke LA. Transgenic mice expressing human glucocerebrosidase variants: utility for the study of Gaucher disease. Blood Cells Mol. Dis. 51(2), 109–115 (2013).
Future Med. Chem. (2014) 6(9)
future science group
Editorial Special Focus Issue: Rare Diseases
Medicinal Chemistry
For reprint orders, please contact [email protected]
Glucocerebrosidase inhibitors: future drugs for the treatment of Gaucher disease? “
The application of inhibitor molecules as intracellular activators of the enzyme in lysosome is a paradigm inherent to pharmacological chaperone therapy approach.
”
Keywords: Gaucher disease • glucocerebrosidase • inhibitors • lysosomal storage disorders • pharmacological chaperone • rare diseaseww
Gaucher disease (GD) is the most widespread lysosomal storage disorder (LSD) caused by a defective activity of β-glucocerebrosidase (GCase; EC 3.2.1.45) [1,2] , the lysosomal β-glucosidase enzyme that catalyzes the hydrolysis of glucosylceramide (GlcCer) into glucose and ceramide. A deficit in enzyme activity results in the accumulation of the glycolipid substrate in macrophages and triggers severe symptoms, such as hepatosplenomegaly, anemia, bone lesions and respiratory failure, and, in more acute cases, affect CNS [3] . Three clinical types of GD have been described based upon the absence (type 1) or the presence and severity (types 2 and 3) of neurological impact [2] . However, recent studies have described the presence of peripheral and central neurological effects in type 1 GD patients [4] ; this has led to the suggestion that GD may be more appropriately described as a continuum of clinical m anifestations rather than distinct subtypes [5] . Therapeutic treatments for GD Current treatment approaches for GD comprise the replacement of the defective enzyme with recombinant enzyme, or the inhibition of the enzyme responsible for GlcCer production [6] . Although these treatments can reduce the symptoms significantly and improve the quality life of type 1 Gaucher patients, they are not reported to be effective on types 2 and 3. Pharmacological chaperone (PC) therapy (PCT) consists of the functional rescuing of misfolded proteins by specific ligands, which, after binding, enhance biosynthesis
10.4155/FMC.14.41 © 2014 Future Science Ltd
and/or prevent/correct premature degradation [7] . PCT either alone or in combination with enzyme replacement, has been proposed as an alternative therapy for GD and other LSDs [8–10] . PCT is based on the use of smallmolecule competitive GCase inhibitors to specifically bind and potentially stabilize catalytically competent GCase variants in the endoplasmic reticulum, assisting mutant protein folding and facilitating the trafficking to the lysosome, where the chaperone–enzyme complex dissociates and the stored GlcCer would be enzymatically degraded. There is an inherent contradiction associated with PCT; it relies on the lysosomal enhancement of enzyme activity with a molecule that inhibits it. In practice, this is resolved by using the molecule at subinhibitory concentrations that are still able to stabilize the protein. Conceptually, rescuing mutated proteins using subinhibitory concentrations of PCs is advantageous when compared with the established therapies. This strategy is based on small molecules, and therefore has the potential for oral bioavailability and blood–brain barrier permeability, and specifically targets the endogenous mutated enzyme to promote a selective activity enhancement. Inhibitors as pharmaceutical chaperones The majority of PC candidates have been selected from GCase competitive inhibitors, which bind to the enzyme active center and reduce the substrate lysosomal degradation. A large variety of molecules have been
Future Med. Chem. (2014) 6(9), 975–978
Ana Trapero Laboratory of Medicinal Chemistry, Department of Biomedicinal Chemistry, Institut de Química Avançada de Catalunya (IQAC–CSIC), Jordi Girona 18-26, 08034 Barcelona, Spain
Amadeu Llebaria Author for correspondence: Laboratory of Medicinal Chemistry, Department of Biomedicinal Chemistry, Institut de Química Avançada de Catalunya (IQAC–CSIC), Jordi Girona 18-26, 08034 Barcelona, Spain Tel.: +34 934 006 108 Fax: +34 932 045 904 amadeu.llebaria@ cid.csic.es
part of
ISSN 1756-8919
975
Editorial Trapero & Llebaria tested as GCase PCs including carbohydrate mimetics (amino cyclitols and iminosugars) or noncarbohydrate compounds discovered by high-throughput screening [8,11–12] . The success of a PC depends significantly on the structure and biophysical properties that determine specificity, affinity and reversibility of protein binding, in addition to membrane permeability and subcellular targeting.
“
Pharmacological chaperone therapy either alone or in combination with enzyme replacement, has been proposed as an alternative therapy for Gaucher disease and other lysosomal storage disorders.
”
PCT is an attractive approach for enhancing enzyme activity and is rapidly evolving towards therapeutic uses. However, several concerns have been raised on its clinical translation. First, most of the PCs reported are active site-directed and, thus, potential inhibitors of target enzymes. In addition, chaperones are usually effective in some missense mutations mainly located in specific enzyme domains, having low or no activity in some others, and are thus potentially appropriate for only a limited number of patients. These problems can be addressed by the identification of novel and allosteric noninhibitory chaperones that stabilize mutant enzymes and promote trafficking out of the endoplasmic reticulum. Allosteric compounds do not bind to the orthosteric substrate binding site, but to an alternatively located site whereby they can potentiate or inhibit the activity of the protein on its natural ligand. Recently, GCase activator compounds binding to allosteric sites and devoid of inhibitory effects have been described [13] , providing the basis for the development of a novel class of PC for GD treatment, which would probably resolve some of the problems associated with active site inhibitors and, thereby, greatly simplify the administration and dosing necessary with maximize enzyme activity. Allosteric ligands for other types of proteins have been successfully developed to drugs, and research is particularly active in G protein-coupled receptors for CNS diseases [14] . The approaches to allosteric molecules for G protein-coupled receptors could be adapted to rare diseases to increase the discovery of new hit compounds. Another problem to therapeutic application of PCs may be the achievement of insufficient enhancement of residual enzyme activity. Most of the PCs reported to date for type 1 GD have similar effects increasing two- to three-fold the residual cellular activity of N370S GCase independently of their affinity for the mutant protein [11] . Treatment with Plicera (Amicus Therapeutics, NJ, USA), the leading clinical candidate for PCT for GD, increased enzymatic activity for all patients enrolled in
976
Future Med. Chem. (2014) 6(9)
a Phase II trial showing a positive safety profile. However, Plicera development was stopped owing to lack of efficacy demonstrating significant clinical improvements in only one patient out of 18 [15] . This result could indicate that the increase of the residual GCase activity achieved with Plicera is too low for therapeutic effectiveness. Although these results were unsatisfactory, the GD patient who demonstrated a clinically significant improvement exemplifies the first proof-of-concept in humans for a PCT treatment of GD. In addition to Plicera, a clinical trial was recently initiated to test the activity of a known drug as a PC for GD. This is a repurposing of ambroxol, a systemically active mucolytic drug that showed positive results in initial in vitro studies [16] ; however, this study has suspended participant recruitment [17] . Another limitation of most of the described compounds as PCs is related to the apparently low potency in GCase activity enhancement in intact cells. Most of the PC candidates are effective in cells at concentrations much higher than those required for isolated enzyme inhibition, although some exceptions exist. The reasons for this are not clear, but can be related to low membrane permeability, unsuitable cell distribution or protein targeting, or a high metabolism, among others. The requirement of high concentrations is a strong limitation on PC’s drug development and is not desirable, owing to toxicity and target selectivity issues, a fact that seriously affects the in vivo tests of the compounds, where dose adjustment is crucial. Moreover, the range of concentrations where a molecule results in enzyme activation before reaching inhibition should be expanded, to ensure that there is a safe therapeutic window. This must allow for a dosing scheme guaranteeing that effective drug concentrations are reached in vivo and also that the target enzyme is not inhibited after proper enzyme folding and trafficking to the lysosome. Furthermore, ADME and the administration mode can affect the time course of the molecule and its activity and it seems reasonable to consider these factors early in the discovery phase.
“
The failure in clinical development of pharmacological chaperones for Gaucher disease and the low number of molecules arriving at clinical phases reflects the difficulties in finding therapies for this disease...
”
In vivo studies evaluating the potential usefulness of a PC for GD are hampered by the difficulties in the development of viable and efficient animal models suitable for testing the PC candidate molecules [18,19] . Most of the GD animal models are obtained by altering the expression or the activity of GCase, and therefore are not
future science group
Glucocerebrosidase inhibitors & Gaucher disease
appropriate to test the enzyme recovery. This represents an important drawback for the preclinical development of PCT candidates, which is being currently addressed [20] and will probably require future research efforts. Future outlook in the design of GCase inhibitors The failure in clinical development of PCs for GD and the low number of molecules arriving at clinical phases reflects the difficulties in finding therapies for this disease and also the special characteristics of enzyme activity enhancement by PCT. Learning the lessons from the past, one can conclude that the evolution of GCase inhibitors hit compounds towards PC leads requires a careful molecule selection and optimization of the strategies in the discovery phase. In addition, the activity profiling assays should be modified to reflect more closely the situation found in GD cells. Currently, most of the activity optimization is being performed testing molecules in wild-type enzyme assays, and measuring the enzyme inhibition in front of unnatural substrates or performing biophysical tests, very often using recombinant purified protein. This approach can be used for a very preliminary screening but is probably too far from the cell and tissue environments with high concentrations of GlcCer and mutated protein found in vivo. This can References 1
Futerman AH, van Meer G. The cell biology of lysosomal storage disorders. Nat. Rev. Mol. Cell Biol. 5(7), 554–565 (2004).
2
Grabowski GA. Phenotype, diagnosis, and treatment of Gaucher’s disease. Lancet 372(9645), 1263–1271 (2008).
3
Zhao H, Grabowski GA. Gaucher disease: perspectives on a prototype lysosomal disease. Cell. Mol. Life Sci. 59(4), 694–707 (2002).
4
Chérin, P, Rose C, de Roux-Serratrice C et al. The neurological manifestations of Gaucher disease type 1: the French Observatoire on Gaucher disease (FROG). J. Inherit. Metab. Dis. 33(4), 331–338 (2010).
lead to misleading outputs and false-positive molecules that will probably fail at a later stage. Finally, in vivo assays with animal models suitable for PCT must be validated to better reproduce the patient disease and treatment situation. The application of inhibitor molecules as intra cellular activators of the enzyme in lysosome is a paradigm inherent to PCT approach. However, the fact that several inhibitors are progressing in PCT clinical trials for LSDs indicates that this does not constitute an unsurmountable problem. Probably the lack of success in GD can be attributed, at least in part, to an inadequate selection and optimization of the lead candidates. This opens prospects for future research to define new molecules having improved properties and to establish assays to better select PCT candidates for this disease. Financial & competing interests disclosure This work was supported by the Spanish MICINN (CTQ201129549-C02-01) and ‘Generalitat de Catalunya’ (grant 2009SGR-1072). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript. 10
Suzuki Y, Ogawa S, Sakakibara Y. Chaperone therapy for neuronopathic lysosomal diseases: competitive inhibitors as chemical chaperones for enhancement of mutant enzyme activities. Perspect. Med. Chem. 3, 7–19 (2009).
11
Trapero A, Llebaria A. Glucocerebrosidase inhibitors for the treatment of Gaucher disease. Future Med. Chem. 5(5), 573–590 (2013).
12
Benito JM, García Fernández JM, Ortiz Mellet C. Pharmacological chaperone therapy for Gaucher disease: a patent review. Expert Opin. Ther. Pat. 21(6), 885–903 (2011).
13
Patnaik S, Zheng W, Choi JH et al. Discovery, structure-activity relationship, and biological evaluation of noninhibitory small molecule chaperones of glucocerebrosidase. J. Med. Chem. 55(12), 5734–5748 (2012).
5
Sidransky E. Gaucher disease: complexity in a ‘simple’ disorder. Mol. Genet. Metab. 83(1–2), 6–15 (2004).
6
Bennett LL, Mohan D. Gaucher disease and its treatment options. Ann. Pharmacother. 47(9), 1182–1193 (2013).
14
7
Leidenheimer NJ, Ryder KG. Pharmacological chaperoning: a primer on mechanism and pharmacology. Pharmacol. Res. 83C, 10–19 (2014).
Conn PJ, Christopoulos A, Lindsley CW. Allosteric modulators of GPCRs: a novel approach for the treatment of CNS disorders. Nat. Rev. Drug Discov. 8(1), 41–54 (2009).
15
Amicus Therapeutics announces preliminary results of Phase II study with plicera for Gaucher disease. http://ir.amicustherapeutics.com/ReleaseDetail. cfm?ReleaseID=413437
16
Maegawa GH, Tropak MB, Buttner JD et al. Identification and characterization of ambroxol as an enzyme enhancement agent for Gaucher disease. J. Biol. Chem. 284(35), 23502–23516 (2009).
8
Boyd RE, Lee G, Rybczynski P et al. Pharmacological chaperones as therapeutics for lysosomal storage diseases. J. Med. Chem. 56(7), 2705–2725 (2013).
9
Parenti G. Treating lysosomal storage diseases with pharmacological chaperones: from concept to clinics. EMBO Mol. Med. 1(5), 268–279 (2009).
future science group
Editorial
www.future-science.com
977
Editorial Trapero & Llebaria
978
17
Clinical Trial of Ambroxol in Patients With Type I Gaucher Disease. http://clinicaltrials.gov/ct2/show/NCT01463215
19
Farfel-Becker T, Vitner EB, Futerman AH. Animal models for Gaucher disease research. Dis. Model. Mech. 4(6), 746–752 (2011).
18
Vaquer G, Rivière F, Mavris M et al. Animal models for metabolic, neuromuscular and ophthalmological rare diseases. Nat. Rev. Drug Discov. 12(4), 287–305 (2013).
20
Sanders A, Hemmelgarn H, Melrose HL, Hein L, Fuller M, Clarke LA. Transgenic mice expressing human glucocerebrosidase variants: utility for the study of Gaucher disease. Blood Cells Mol. Dis. 51(2), 109–115 (2013).
Future Med. Chem. (2014) 6(9)
future science group
