Abstract:
:In 2010, the National Institutes of Health (NIH) established the Therapeutics for Rare and Neglected Diseases (TRND) program within the National Center for Advancing Translational Sciences (NCATS), which was created to stimulate drug discovery and development for rare and neglected tropical diseases through a collaborative model between the NIH, academic scientists, nonprofit organizations, and pharmaceutical and biotechnology companies. This paper describes one of the first TRND programs, the development of 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) for the treatment of Niemann-Pick disease type C1 (NPC1). NPC is a neurodegenerative, autosomal recessive rare disease caused by a mutation in either the NPC1 (about 95% of cases) or the NPC2 gene (about 5% of cases). These mutations affect the intracellular trafficking of cholesterol and other lipids, which leads to a progressive accumulation of unesterified cholesterol and glycosphingolipids in the CNS and visceral organs. Affected individuals typically exhibit ataxia, swallowing problems, seizures, and progressive impairment of motor and intellectual function in early childhood, and usually die in adolescence. There is no disease modifying therapy currently approved for NPC1 in the US. A collaborative drug development program has been established between TRND, public and private partners that has completed the pre-clinical development of HP-β-CD through IND filing for the current Phase I clinical trial that is underway. Here we discuss how this collaborative effort helped to overcome scientific, clinical and financial challenges facing the development of new drug treatments for rare and neglected diseases, and how it will incentivize the commercialization of HP-β-CD for the benefit of the NPC patient community.
journal_name
Curr Top Med Chemjournal_title
Current topics in medicinal chemistryauthors
Ottinger EA,Kao ML,Carrillo-Carrasco N,Yanjanin N,Shankar RK,Janssen M,Brewster M,Scott I,Xu X,Cradock J,Terse P,Dehdashti SJ,Marugan J,Zheng W,Portilla L,Hubbs A,Pavan WJ,Heiss J,Vite CH,Walkley SU,Ory DS,Silbedoi
10.2174/1568026613666131127160118subject
Has Abstractpub_date
2014-01-01 00:00:00pages
330-9issue
3eissn
1568-0266issn
1873-4294pii
CTMC-EPUB-57725journal_volume
14pub_type
杂志文章,评审abstract::Transition metal complexes with terpyridine ligands have attracted a widespread interest with respect to biomedical applications: [(tpy)PtCl]Cl and [(tpy)RuCl(3)] are potent anti-tumor agents with activities comparable to those of cisplatin and carboplatin. The Ru(II) complexes feature a high potential as reactive pro...
journal_title:Current topics in medicinal chemistry
pub_type: 杂志文章,评审
doi:10.2174/156802612799078919
更新日期:2012-01-01 00:00:00
abstract:: ...
journal_title:Current topics in medicinal chemistry
pub_type: 社论
doi:10.2174/156802661921191024120954
更新日期:2019-01-01 00:00:00
abstract::Escherichia coli purine nucleoside phosphorylase (PNP) catalyzes the cleavage of 9-(2-deoxy-beta-D-ribofuranosyl)-6-methylpurine (MeP-dR), while human PNP does not. MeP-dR is well tolerated while the cleavage product, 6-methylpurine (MeP), is highly cytotoxic. This clinical profile suggests an anticancer gene therapy ...
journal_title:Current topics in medicinal chemistry
pub_type: 杂志文章,评审
doi:10.2174/156802605774463105
更新日期:2005-01-01 00:00:00
abstract::Pyrola (Pyrolaceae), also known as Luxiancao/in China, was recorded in Sheng Nong's Herbal Classic listed in top grade. Pyrola herbs were used as medicinal plants for a long history with wide-ranging activities such as nourishing kidney-yang, strengthening muscles and bones, activating blood, stopping bleeding, dispel...
journal_title:Current topics in medicinal chemistry
pub_type: 杂志文章,评审
doi:10.2174/1568026619666191203112412
更新日期:2020-01-01 00:00:00
abstract::The IkappaB kinases (IKKs) are essential components of the signaling pathway by which the NF-kappaB p50/RelA transcription factor is activated in response to pro-inflammatory stimuli such as lipopolysaccharide (LPS) and tumor necrosis factor (TNFalpha). NF-kappaB signaling results in the expression of numerous genes i...
journal_title:Current topics in medicinal chemistry
pub_type: 杂志文章,评审
doi:10.2174/156802609789007336
更新日期:2009-01-01 00:00:00
abstract::Structure-activity relationships of a 4-aminoquinoline MCH-1R antagonist lead series were explored by synthesis of analogs with modifications at the 2-, 4- and 6-positions of the original HTS hit. Improvements to the original screening lead were made by addition of lipophilic groups at the 2-position and biphenyl, cyc...
journal_title:Current topics in medicinal chemistry
pub_type: 杂志文章,评审
doi:10.2174/156802607782194789
更新日期:2007-01-01 00:00:00
abstract::Aptamers- short nucleic acid or peptide ligands- attracted considerable attention across various disciplines as target specific therapeutic, delivery vehicle and diagnostic tools. The applicability of aptamers - often termed as 'chemical antibodies' - continues to grow and possess certain edge over the antibody counte...
journal_title:Current topics in medicinal chemistry
pub_type: 社论
doi:10.2174/1568026615666150413161707
更新日期:2015-01-01 00:00:00
abstract::Several strategies used in the rational design and synthesis of fluorinated compounds as potential therapeutic agents are reviewed. Applications of fluorine substitution in empirical SAR studies for lead development also are discussed, along with the implications with respect to fluorine target interactions that can b...
journal_title:Current topics in medicinal chemistry
pub_type: 杂志文章,评审
doi:10.2174/156802606777951073
更新日期:2006-01-01 00:00:00
abstract::Research over the years has gradually and sequentially highlighted contributory role of hypothalamic- based kisspeptin-signaling axis as a major positive modulator of the neuroendocrinological reproductive axis in mammals. However, a series of landmark studies provided convincing evidence of role of this signaling in ...
journal_title:Current topics in medicinal chemistry
pub_type: 杂志文章,评审
doi:10.2174/1568026616666160212123309
更新日期:2016-01-01 00:00:00
abstract::Chagas disease and African sleeping sickness are trypanosomal infections that represent important public health problems in Latin America and Africa, respectively. The restriction of these diseases to the poorer parts of the world has meant that they have been largely neglected and limited progress has been made in th...
journal_title:Current topics in medicinal chemistry
pub_type: 杂志文章,评审
doi:10.2174/156802611796575894
更新日期:2011-01-01 00:00:00
abstract::A large number of human disorders are caused by defects in protein folding resulting from genetic mutations or adverse physiological conditions, and these are collectively referred to protein misfolding diseases. Such disorders imply dysfunction of a cellular process either as a result of a toxic gain of function due ...
journal_title:Current topics in medicinal chemistry
pub_type: 杂志文章,评审
doi:10.2174/1568026611212220002
更新日期:2012-01-01 00:00:00
abstract::Pulmonary drug delivery represents the best way of treating lung diseases, since it allows direct delivery of the drug to the site of action, with few systemic effects. Meanwhile, the lungs may be used as a portal of entry to the body, allowing systemic delivery of drugs via the airway surfaces into the bloodstream. I...
journal_title:Current topics in medicinal chemistry
pub_type: 杂志文章,评审
doi:10.2174/1568026615666150108123256
更新日期:2015-01-01 00:00:00
abstract::This review discusses the state of the art, challenges and perspectives in recent applications of electrochemistry in the life sciences. It deals mainly with the elucidation of molecular mechanisms of drug action, drug design and development, involving electron transfer, pharmaco-electrochemistry (the combination of e...
journal_title:Current topics in medicinal chemistry
pub_type: 杂志文章,评审
doi:
更新日期:2015-01-01 00:00:00
abstract::The dopamine transporter (DAT) is a target for the development of pharmacotherapies for a number of central disorders including Parkinson's disease, Alzheimer's disease, schizophrenia, Tourette's syndrome, Lesch-Nyhan disease, attention deficit hyperactivity disorder (ADHD), obesity, depression, and stimulant abuse as...
journal_title:Current topics in medicinal chemistry
pub_type: 杂志文章,评审
doi:10.2174/156802606778249775
更新日期:2006-01-01 00:00:00
abstract::A major neurotransmitter, L-Glutamate must be stored, transported and received, and these processes are mediated by proteins that bind this simple yet essential amino acid. Detailed evidence continues to emerge on the structure of Glu binding proteins, which includes both receptors and transporters. It appears that re...
journal_title:Current topics in medicinal chemistry
pub_type: 杂志文章,评审
doi:10.2174/156802606777057535
更新日期:2006-01-01 00:00:00
abstract::At present, a limited number of strategies exist for diagnostic imaging of patients with bacterial infection. While radiolabeled probes and white blood cells provide robust solutions to detect bacteria in humans, they also give false positives in cases of sterile inflammation. With the onset of bacterial drug resistan...
journal_title:Current topics in medicinal chemistry
pub_type: 杂志文章,评审
doi:10.2174/1568026611313040008
更新日期:2013-01-01 00:00:00
abstract::L-DOPA is a di-hydroxy-phenyl, catecholamine precursor, amino acid, initially considered as an inert compound and now the key stone for the treatment of Parkinson's disease (PD) and some hereditary dystonias. L-DOPA, when administered to mammals, is rapidly metabolized to dopamine and 3-OM-DOPA, and its half-life in p...
journal_title:Current topics in medicinal chemistry
pub_type: 杂志文章,评审
doi:
更新日期:2009-01-01 00:00:00
abstract::Degenerative diseases are becoming more common with increasing life expectancy of the human population. The 20th century faced a progressive demographic change in the industrialized world, followed by identical trends in population aging in Asia, Africa, and Middle and South America. A significant increase in chronic ...
journal_title:Current topics in medicinal chemistry
pub_type: 杂志文章,评审
doi:10.2174/1568026618666171215094029
更新日期:2017-01-01 00:00:00
abstract::Release of somatostatin into the circulation from the activated TRPV1-expressing nociceptors revealed by antidromic stimulation of dorsal roots in the rat pinpointed to a novel potential drug target on these nociceptors. The review summarizes the functional, biochemical and pharmacological evidence for a novel somatos...
journal_title:Current topics in medicinal chemistry
pub_type: 杂志文章,评审
doi:10.2174/156802611796904852
更新日期:2011-01-01 00:00:00
abstract::(2R,3R)-2,3-Butanediol has many industrial applications, such as it is used as an antifreeze agent and low freezing point fuel. In addition, it is particularly important to provide chiral groups in drugs. In recent years, this valuable bio-based chemical has attracted increasing attention, and significant progress has...
journal_title:Current topics in medicinal chemistry
pub_type: 杂志文章,评审
doi:10.2174/1568026617666170504101646
更新日期:2017-01-01 00:00:00
abstract::As the first stable tachysterol analogs, 14-epi-19-nortachysterol and its 2-substituted derivatives were synthesized using the Stille coupling reaction between the A-ring precursor (three vinylstannanes) and the CD-ring vinyl trifrate. Among them, the 2-methylidene group was hydrogenated with Wilkinson's catalyst regi...
journal_title:Current topics in medicinal chemistry
pub_type: 杂志文章
doi:10.2174/1568026615666141208103741
更新日期:2014-01-01 00:00:00
abstract::Dementia is an increasing health problem in older aged populations worldwide. Age-related changes in the brain can be observed decades before the first symptoms of cognitive decline appear. Cognitive impairment has chronic inflammatory components, which can be enhanced by systemic immune activation. There exist mutual...
journal_title:Current topics in medicinal chemistry
pub_type: 杂志文章
doi:10.2174/1568026620666200514090359
更新日期:2020-01-01 00:00:00
abstract::Thematic Analysis™ is a chemogenomic tool which has been developed and used to aid the process of GPCR drug discovery. This review covers the scientific rationale behind the development of this tool and provides examples of the successful application of the chemogenomic method in both hit finding and hit to lead stage...
journal_title:Current topics in medicinal chemistry
pub_type: 杂志文章,评审
doi:10.2174/156802611796391302
更新日期:2011-01-01 00:00:00
abstract::Target-Related Affinity Profiling (TRAP) is a computational drug discovery technology that is based on 'affinity fingerprints', which are molecular descriptors derived from the protein binding preferences of small molecules. The underlying concepts of TRAP are reviewed. Affinity fingerprints are compared to molecular ...
journal_title:Current topics in medicinal chemistry
pub_type: 杂志文章,评审
doi:10.2174/1568026053828394
更新日期:2005-01-01 00:00:00
abstract::The genetics of Alzheimer's disease (AD) implies that restoring non-pathological levels or ratios of different amyloid-beta (Abeta) peptide species in the brain could prevent the onset or delay the progression of this neurodegenerative disease. In particular, a selective reduction of the longer Abeta(1-42) peptide whi...
journal_title:Current topics in medicinal chemistry
pub_type: 杂志文章,评审
doi:10.2174/156802608783334051
更新日期:2008-01-01 00:00:00
abstract:BACKGROUND:Neuraminidase inhibitors (NAIs) are the only class of antivirals in clinical use against influenza virus approved worldwide. However, approximately 1-3% of circulating strains present resistance mutations to oseltamivir (OST), the most used NAI. Therefore, it is important to catalogue new molecules to inhibi...
journal_title:Current topics in medicinal chemistry
pub_type: 杂志文章
doi:10.2174/1568026620666191219150738
更新日期:2020-01-01 00:00:00
abstract::Cathepsin S has been of increasing interest as a target of medicinal chemistry efforts given its role in modulating antigen-presentation by major histocompatibility class II (MHC II) molecules as well as its involvement in extracellular proteolytic activities. Inhibition of the cathepsin S enzyme reduces degradation o...
journal_title:Current topics in medicinal chemistry
pub_type: 杂志文章,评审
doi:10.2174/156802610791113432
更新日期:2010-01-01 00:00:00
abstract:BACKGROUND:Candida species are the important etiologic agents for candidiasis, the most prevalent cause of opportunistic fungal infections. Candida invasion results in mucosal to systemic infections through immune dysfunction and helps in further invasion and proliferation at several sites in the host. The host defence...
journal_title:Current topics in medicinal chemistry
pub_type: 杂志文章,评审
doi:10.2174/1568026619666191026105308
更新日期:2019-01-01 00:00:00
abstract::Homologation is a concept introduced by Gerhard in 1853 to describe a homologous series in organic chemistry. Since then, the concept has been adapted and used in medicinal chemistry as one of the most important strategies for molecular modification. The homologation types, their influence on physico-chemical properti...
journal_title:Current topics in medicinal chemistry
pub_type: 杂志文章,评审
doi:10.2174/1568026619666190808145235
更新日期:2019-01-01 00:00:00
abstract:BACKGROUND:Development of acetyl- (AChE) and butyrylcholinesterase (BuChE) inhibitors belongs to viable strategies for the treatment of dementia and other diseases related to decrease in cholinergic neurotransmission. OBJECTIVE:That is why we designed twenty-two analogues of a dual AChEBuChE salicylanilide inhibitor, ...
journal_title:Current topics in medicinal chemistry
pub_type: 杂志文章
doi:10.2174/1568026620666200819154722
更新日期:2020-01-01 00:00:00