Lead Optimization of Benzoxazolone Carboxamides as Orally Bioavailable and CNS Penetrant Acid Ceramidase Inhibitors

Martino, Simona Di; Tardia, Piero; Cilibrasi, Vincenzo; Caputo, Samantha; Mazzonna, Marco; Russo, Debora; Realini, Natalia; Margaroli, Natasha; Migliore, Marco; Pizzirani, Daniela; Ottonello, Giuliana; Bertozzi, Sine Mandrup; Armirotti, Andrea; Nguyễn, Duy Anh; Sun, Ying; Bongarzone, Ernesto R.; Lansbury, Peter T.; Liu, Min; Skerlj, Renato T.

doi:10.1021/acs.jmedchem.9b02004

Cited by 11 publications

(18 citation statements)

References 57 publications

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“…Pharmacological inhibition of ACD with the anti-cancer drug, carmofur, reduced psychosine levels and increased the life span of Twitcher mice, thus validating ACD as an SRT target. Interestingly, a recent report by Martino et al, (2020) describes the creation of a new class of compounds with drug-like properties that efficiently inhibit ACD and decreases psychosine levels in the brains of Twitcher mice [ 39 ]. Another potential SRT target for Krabbe disease is ceramide galactosyltransferase (CGT).…”

Section: The Evolution and Current Status Of Therapies For Krabbe Diseasementioning

confidence: 99%

“…Based on studies in the murine model, it would be of interest to determine if BMT provides more complete correction of disease in the canine model, particularly in combination with lower doses of AAV. Additionally, SRT using ACD inhibitors was recently shown to reduce psychosine in the brain of Twitcher mice [ 39 ]. With once-a-day intraperitoneal injection, Twitcher mice showed a strong dose response between 30 and 90 mg/kg of the inhibitor.…”

Section: The Evolution and Current Status Of Therapies For Krabbe Diseasementioning

confidence: 99%

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Krabbe disease: New hope for an old disease

Bradbury

Bongarzone

Sands

2021

Neuroscience Letters

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Krabbe disease (globoid cell leukodystrophy) is a lysosomal storage disease (LSD) characterized by progressive and profound demyelination. Infantile, juvenile and adult-onset forms of Krabbe disease have been described, with infantile being the most common. Children with an infantile-onset generally appear normal at birth but begin to miss developmental milestones by si x months of age and die by two to four years of age. Krabbe disease is caused by a deficiency of the acid hydrolase galactosylceramidase (GALC) which is responsible for the degradation of galactosylceramides and sphingolipids, which are abundant in myelin membranes. The absence of GALC leads to the to x ic accumulation of galactosylsphingosine (psychosine), a lysoderivative of galactosylceramides, in oligodendrocytes and Schwann cells resulting in demyelination of the central and peripheral nervous systems, respectively. Treatment strategies such as enzyme replacement, substrate reduction, enzyme chaperones, and gene therapy have shown promise in LSDs. Unfortunately, Krabbe disease has been relatively refractory to most single-therapy interventions. Although hematopoietic stem cell transplantation can alter the course of Krabbe disease and is the current standard-of-care, it simply slows the progression, even when initiated in presymptomatic children. However, the recent success of combinatorial therapeutic approaches in small animal models of Krabbe disease and the identification of new pathogenic mechanisms provide hope for the development of effective treatments for this devastating disease. This review provides a brief history of Krabbe disease and the evolution of single and combination therapeutic approaches and discusses new pathogenic mechanisms and how they might impact the development of more effective treatment strategies.

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Section: The Evolution and Current Status Of Therapies For Krabbe Diseasementioning

confidence: 99%

Section: The Evolution and Current Status Of Therapies For Krabbe Diseasementioning

confidence: 99%

Krabbe disease: New hope for an old disease

Bradbury

Bongarzone

Sands

2021

Neuroscience Letters

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“…Studies to develop an acid ceramidase inhibitor with optimal properties are actively being pursued. Toward this goal, the development of benzoxazolone carboxamides led to piperidine 22 m, which can cross into the CNS and can be delivered by the oral route ( 68 ). This inhibitor reduced both psychosine levels in the brains of twitcher mice and glucosylsphingosine levels in a mouse model of Gaucher disease ( 68 ).…”

Section: Substrate Reduction Therapy Targeting Acid Ceramidasementioning

confidence: 99%

“…Toward this goal, the development of benzoxazolone carboxamides led to piperidine 22 m, which can cross into the CNS and can be delivered by the oral route ( 68 ). This inhibitor reduced both psychosine levels in the brains of twitcher mice and glucosylsphingosine levels in a mouse model of Gaucher disease ( 68 ). Additional compounds that inhibit acid ceramidase are also being developed ( 69 ).…”

Section: Substrate Reduction Therapy Targeting Acid Ceramidasementioning

confidence: 99%

Substrate Reduction Therapy for Krabbe Disease: Exploring the Repurposing of the Antibiotic D-Cycloserine

Levine

Tsau

2022

Front. Pediatr.

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Krabbe disease is a lysosomal storage disease that is caused by a deficiency in galactosylceramidase. Infantile onset disease is the most common presentation, which includes progressive neurological deterioration with corresponding demyelination, development of globoid cells, astrocyte gliosis, etc. Hemopoietic stem cell transplantation (HSCT) is a disease modifying therapy, but this intervention is insufficient with many patients still experiencing developmental delays and progressive deterioration. Preclinical studies have used animal models, e.g., twitcher mice, to test different experimental therapies resulting in developments that have led to progressive improvements in the therapeutic impact. Some recent advances have been in the areas of gene therapy and substrate reduction therapy (SRT), as well as using these in combination with HSCT. Unfortunately, new experimental approaches have encountered obstacles which have impeded the translation of novel therapies to human patients. In an effort to identify a safe adjunct therapy, D-cycloserine was tested in preliminary studies in twitcher mice. When administered as a standalone therapy, D-cycloserine was shown to lengthen the lifespan of twitcher mice in a small but significant manner. D-Cycloserine is an FDA approved antibiotic used for drug resistant tuberculosis. It also acts as a partial agonist of the NMDA receptor, which has led to numerous human studies for a range of neuropsychiatric and neurological conditions. In addition, D-cycloserine may inhibit serine palmitoyltransferase (SPT), which catalyzes the rate-limiting step in sphingolipid production. The enantiomer, L-cycloserine, is a much more potent inhibitor of SPT than D-cycloserine. Previously, L-cycloserine was found to act as an effective SRT agent in twitcher mice as both a standalone therapy and as part of combination therapies. L-Cycloserine is not approved for human use, and its potent inhibitory properties may limit its ability to maintain a level of partial inactivation of SPT that is also safe. In theory, D-cycloserine would encompass a much broader dosage range to achieve a safe degree of partial inhibition of SPT, which increases the likelihood it could advance to human studies in patients with Krabbe disease. Furthermore, additional properties of D-cycloserine raise the possibility of other therapeutic mechanisms that could be exploited for the treatment of this disease.

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“…A thorough review of substrate reduction therapies for KD has been published and is an excellent resource for a commentary on this therapeutic strategy ( 114 ). More recently, acid ceramidase inhibitors have showed significant reductions in brain psychosine levels in Twitcher mice and could be promising, particularly in combination with other therapeutic strategies ( 115 ). In general, however, substrate reduction therapies on their own have shown limited efficacy in preclinical models, and have not yet been tested in human KD patients, though they could be beneficial if used in conjunction with other approaches such as gene therapy.…”

Section: Therapeutic Strategiesmentioning

confidence: 99%

Krabbe Disease: Prospects of Finding a Cure Using AAV Gene Therapy

Nasir¹,

Chopra²,

Elwood³

et al. 2021

Front. Med.

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Krabbe Disease (KD) is an autosomal metabolic disorder that affects both the central and peripheral nervous systems. It is caused by a functional deficiency of the lysosomal enzyme, galactocerebrosidase (GALC), resulting in an accumulation of the toxic metabolite, psychosine. Psychosine accumulation affects many different cellular pathways, leading to severe demyelination. Although there is currently no effective therapy for Krabbe disease, recent gene therapy-based approaches in animal models have indicated a promising outlook for clinical treatment. This review highlights recent findings in the pathogenesis of Krabbe disease, and evaluates AAV-based gene therapy as a promising strategy for treating this devastating pediatric disease.

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Lead Optimization of Benzoxazolone Carboxamides as Orally Bioavailable and CNS Penetrant Acid Ceramidase Inhibitors

Cited by 11 publications

References 57 publications

Krabbe disease: New hope for an old disease

Krabbe disease: New hope for an old disease

Substrate Reduction Therapy for Krabbe Disease: Exploring the Repurposing of the Antibiotic D-Cycloserine

Krabbe Disease: Prospects of Finding a Cure Using AAV Gene Therapy

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