Search results for: Richard B. Silverman

Items from 1 to 20 out of 139 results

article

Small molecules targeting different cellular pathologies for the treatment of amyotrophic lateral sclerosis

Mohamed F. Elmansy, Cory T. Reidl, Mizzanoor Rahaman, P. Hande Özdinler, more

Medicinal Research Reviews > 43 > 6 > 2260 - 2302

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease in which the motor neuron circuitry displays progressive degeneration, affecting mostly the motor neurons in the brain and in the spinal cord. There are no effective cures, albeit three drugs, riluzole, edaravone, and AMX0035 (a combination of sodium phenylbutyrate and taurursodiol), have been approved by the Food and Drug...

article

OV329, a novel highly potent γ‐aminobutyric acid aminotransferase inactivator, induces pronounced anticonvulsant effects in the pentylenetetrazole seizure threshold test and in amygdala‐kindled rats

Malte Feja, Sebastian Meller, Lillian S. Deking, Edith Kaczmarek, more

Epilepsia > 62 > 12 > 3091 - 3104

Objective An attractive target to interfere with epileptic brain hyperexcitability is the enhancement of γ‐aminobutyric acidergic (GABAergic) inhibition by inactivation of the GABA‐metabolizing enzyme GABA aminotransferase (GABA‐AT). GABA‐AT inactivators were designed to control seizures by raising brain GABA levels. OV329, a novel drug candidate for the treatment of epilepsy and addiction, has been...

article

Physiological involvement of presynaptic L‐type voltage‐dependent calcium channels in GABA release of cerebellar molecular layer interneurons

Stéphanie Rey, Gilliane Maton, Shin’Ichiro Satake, Isabel Llano, more

Journal of Neurochemistry > 155 > 4 > 390 - 402

Abstract While high threshold voltage‐dependent Ca²⁺ channels (VDCCs) of the N and P/Q families are crucial for evoked neurotransmitter release in the mammalian CNS, it remains unclear to what extent L‐type Ca²⁺ channels (LTCCs), which have been mainly considered as acting at postsynaptic sites, participate in the control of transmitter release. Here, we investigate the possible role of LTCCs in...

article

(S)‐4‐Amino‐5‐phenoxypentanoate designed as a potential selective agonist of the bacterial transcription factor GabR

Daniel S. Catlin, Cory T. Reidl, Thomas R. Trzupek, Richard B. Silverman, more

Protein Science > 29 > 8 > 1816 - 1828

Addressing molecular recognition in the context of evolution requires pursuing new molecular targets to enable the development of agonists or antagonists with new mechanisms of action. Disruption of transcriptional regulation through targeting transcription factors that regulate the expression of key enzymes in bacterial metabolism may provide a promising method for controlling the bacterial metabolic...

article

Inducible nitric oxide synthase: Regulation, structure, and inhibition

Maris A. Cinelli, Ha T. Do, Galen P. Miley, Richard B. Silverman

Medicinal Research Reviews > 40 > 1 > 158 - 189

A considerable number of human diseases have an inflammatory component, and a key mediator of immune activation and inflammation is inducible nitric oxide synthase (iNOS), which produces nitric oxide (NO) from l‐arginine. Overexpressed or dysregulated iNOS has been implicated in numerous pathologies including sepsis, cancer, neurodegeneration, and various types of pain. Extensive knowledge has been...

article

Nitric Oxide Synthase as a Target for Methicillin-Resistant Staphylococcus aureus

Jeffrey K. Holden, Soosung Kang, Federico C. Beasley, Maris A. Cinelli, more

Chemistry & Biology > 2015 > 22 > 6 > 785-792

Bacterial infections associated with methicillin-resistant Staphylococcus aureus (MRSA) are a major economic burden to hospitals, and confer high rates of morbidity and mortality among those infected. Exploitation of novel therapeutic targets is thus necessary to combat this dangerous pathogen. Here, we report on the identification and characterization, including crystal structures, of two nitric...

article

Ornithine Aminotransferase versus GABA Aminotransferase: Implications for the Design of New Anticancer Drugs

Hyunbeom Lee, Jose I. Juncosa, Richard B. Silverman

Medicinal Research Reviews > 35 > 2 > 286 - 305

Ornithine aminotransferase (OAT) and γ‐aminobutyric acid aminotransferase (GABA‐AT) are classified under the same evolutionary subgroup and share a large portion of structural, functional, and mechanistic features. Therefore, it is not surprising that many molecules that bind to GABA‐AT also bind well to OAT. Unlike GABA‐AT, OAT had not been viewed as a potential therapeutic target until recently;...

article

Synthesis of mevalonate- and fluorinated mevalonate prodrugs and their in vitro human plasma stability

Soosung Kang, Mizuki Watanabe, J.C. Jacobs, Masaya Yamaguchi, more

European Journal of Medicinal Chemistry > 2015 > 90 > Complete > 448-461

The mevalonate pathway is essential for the production of many important molecules in lipid biosynthesis. Inhibition of this pathway is the mechanism of statin cholesterol-lowering drugs, as well as the target of drugs to treat osteoporosis, to combat parasites, and to inhibit tumor cell growth. Unlike the human mevalonate pathway, the bacterial pathway appears to be regulated by diphosphomevalonate...

article

Deuteration and fluorination of 1,3-bis(2-phenylethyl)pyrimidine-2,4,6(1H,3H,5H)-trione to improve its pharmacokinetic properties

Guoyao Xia, Radhia Benmohamed, Richard I. Morimoto, Donald R. Kirsch, more

Bioorganic & Medicinal Chemistry Letters > 2014 > 24 > 21 > 5098-5101

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of motor neurons, leading to muscle weakness, paralysis, and death, most often from respiratory failure. Over 200 pyrimidine-2,4,6-trione (PYT) small molecules, which prevent aggregation and reduce the associated toxicity of mutant superoxide dismutase 1 (SOD1) found in patients with familial...

article

Combination of chiral linkers with thiophenecarboximidamide heads to improve the selectivity of inhibitors of neuronal nitric oxide synthase

Qing Jing, Huiying Li, Linda J. Roman, Pavel Martásek, more

Bioorganic & Medicinal Chemistry Letters > 2014 > 24 > 18 > 4504-4510

To develop potent and selective nNOS inhibitors, a new series of double-headed molecules with chiral linkers that derive from natural amino acid derivatives have been designed and synthesized. The new structures integrate a thiophenecarboximidamide head with two types of chiral linkers, presenting easy synthesis and good inhibitory properties. Inhibitor (S)-9b exhibits a potency of 14.7nM against...

article

nNOS inhibition during profound asphyxia reduces seizure burden and improves survival of striatal phenotypic neurons in preterm fetal sheep

Paul P. Drury, Joanne O. Davidson, Sam Mathai, Lotte G. van den Heuij, more

Neuropharmacology > 2014 > 83 > Complete > 62-70

Basal ganglia injury after hypoxia-ischemia remains common in preterm infants, and is closely associated with later cerebral palsy. In the present study we tested the hypothesis that a highly selective neuronal nitric oxide synthase (nNOS) inhibitor, JI-10, would improve survival of striatal phenotypic neurons after profound asphyxia, and that the subsequent seizure burden and recovery of EEG are...

article

Development and characterization of 3-(benzylsulfonamido)benzamides as potent and selective SIRT2 inhibitors

Mohammad A. Khanfar, Luisa Quinti, Hua Wang, Soo Hyuk Choi, more

European Journal of Medicinal Chemistry > 2014 > 76 > Complete > 414-426

Inhibitors of sirtuin-2 deacetylase (SIRT2) have been shown to be protective in various models of Huntington's disease (HD) by decreasing polyglutamine aggregation, a hallmark of HD pathology. The present study was directed at optimizing the potency of SIRT2 inhibitors containing the neuroprotective sulfobenzoic acid scaffold and improving their pharmacology. To achieve that goal, 176 analogues were...

article

Corrigendum to “Substituted pyrazolones require N2 hydrogen bond donating ability to protect against cytotoxicity from protein aggregation of mutant superoxide dismutase 1” [Bioorg. Med. Chem. Lett. 22 (2012) 6647–6650]

Paul C. Trippier, Radhia Benmohamed, Donald R. Kirsch, Richard B. Silverman

Bioorganic & Medicinal Chemistry Letters > 2014 > 24 > 2 > 691

article

Partial neuroprotection by nNOS inhibition during profound asphyxia in preterm fetal sheep

Paul P. Drury, Joanne O. Davidson, Lotte G. van den Heuij, Sidhartha Tan, more

Experimental Neurology > 2013 > 250 > Complete > 282-292

Preterm brain injury is partly associated with hypoxia–ischemia starting before birth. Excessive nitric oxide production during HI may cause nitrosative stress, leading to cell membrane and mitochondrial damage. We therefore tested the hypothesis that therapy with a new, selective neuronal nitric oxide synthase (nNOS) inhibitor, JI-10 (0.022mg/kg bolus, n=8), given 30min before 25min of complete umbilical...

article

Chiral linkers to improve selectivity of double-headed neuronal nitric oxide synthase inhibitors

Qing Jing, Huiying Li, Georges Chreifi, Linda J. Roman, more

Bioorganic & Medicinal Chemistry Letters > 2013 > 23 > 20 > 5674-5679

To develop potent and selective nNOS inhibitors, new double-headed molecules with chiral linkers that derive from natural amino acids or their derivatives have been designed. The new structures contain two ether bonds, which greatly simplifies the synthesis and accelerates structure optimization. Inhibitor (R)-6b exhibits a potency of 32nM against nNOS and is 475 and 244 more selective for nNOS over...

article

Two continuous coupled assays for ornithine-δ-aminotransferase

Jose I. Juncosa, Hyunbeom Lee, Richard B. Silverman

Analytical Biochemistry > 2013 > 440 > 2 > 145-149

We have developed two new continuous coupled assays for ornithine-δ-aminotransferase (OAT) that are more sensitive than previous methods, measure activity in real time, and can be carried out in multiwell plates for convenience and high throughput. The first assay is based on the reduction of Δ ¹ -pyrroline-5-carboxylate (P5C), generated from ornithine by OAT, using human pyrroline 5-carboxylate...

article

In search of potent and selective inhibitors of neuronal nitric oxide synthase with more simple structures

Qing Jing, Huiying Li, Jianguo Fang, Linda J. Roman, more

Bioorganic & Medicinal Chemistry > 2013 > 21 > 17 > 5323-5331

In certain neurodegenerative diseases damaging levels of nitric oxide (NO) are produced by neuronal nitric oxide synthase (nNOS). It, therefore, is important to develop inhibitors selective for nNOS that do not interfere with other NOS isoforms, especially endothelial NOS (eNOS), which is critical for proper functioning of the cardiovascular system. While we have been successful in developing potent...

article

Antagonism of L-type Ca2+ channels CaV1.3 and CaV1.2 by 1,4-dihydropyrimidines and 4H-pyrans as dihydropyridine mimics

Soosung Kang, Garry Cooper, Sara Fernandez Dunne, Chi-Hao Luan, more

Bioorganic & Medicinal Chemistry > 2013 > 21 > 14 > 4365-4373

The L-type calcium channel (LTCC) Ca _V 1.3 is regarded as a new potential therapeutic target for Parkinson’s disease. Calcium influx through Ca _V 1.3 LTCC during autonomous pacemaking in adult dopaminergic neurons of the substantia nigra pars compacta is related to the generation of mitochondrial oxidative stress in animal models. Development of a Ca _V 1.3 antagonist selective...

article

Cyclopropyl- and methyl-containing inhibitors of neuronal nitric oxide synthase

Huiying Li, Fengtian Xue, James M. Kraus, Haitao Ji, more

Bioorganic & Medicinal Chemistry > 2013 > 21 > 5 > 1333-1343

Inhibitors of neuronal nitric oxide synthase have been proposed as therapeutics for the treatment of different types of neurological disorders. On the basis of a cis-3,4-pyrrolidine scaffold, a series of trans-cyclopropyl- and methyl-containing nNOS inhibitors have been synthesized. The insertion of a rigid electron-withdrawing cyclopropyl ring decreases the basicity of the adjacent amino group, which...

article

Probing the steric requirements of the γ-aminobutyric acid aminotransferase active site with fluorinated analogues of vigabatrin

Jose I. Juncosa, Andrew P. Groves, Guoyao Xia, Richard B. Silverman

Bioorganic & Medicinal Chemistry > 2013 > 21 > 4 > 903-911

We have synthesized three analogues of 4-amino-5-fluorohexanoic acids as potential inactivators of γ-aminobutyric acid aminotransferase (GABA-AT), which were designed to combine the potency of their shorter chain analogue, 4-amino-5-fluoropentanoic acid (AFPA), with the greater enzyme selectivity of the antiepileptic vigabatrin (Sabril®). Unexpectedly, these compounds failed to inactivate or inhibit...

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INFONA - science communication portal

Search results for: Richard B. Silverman

Small molecules targeting different cellular pathologies for the treatment of amyotrophic lateral sclerosis

OV329, a novel highly potent γ‐aminobutyric acid aminotransferase inactivator, induces pronounced anticonvulsant effects in the pentylenetetrazole seizure threshold test and in amygdala‐kindled rats

Physiological involvement of presynaptic L‐type voltage‐dependent calcium channels in GABA release of cerebellar molecular layer interneurons

(S)‐4‐Amino‐5‐phenoxypentanoate designed as a potential selective agonist of the bacterial transcription factor GabR

Inducible nitric oxide synthase: Regulation, structure, and inhibition

Nitric Oxide Synthase as a Target for Methicillin-Resistant Staphylococcus aureus

Ornithine Aminotransferase versus GABA Aminotransferase: Implications for the Design of New Anticancer Drugs

Synthesis of mevalonate- and fluorinated mevalonate prodrugs and their in vitro human plasma stability

Deuteration and fluorination of 1,3-bis(2-phenylethyl)pyrimidine-2,4,6(1H,3H,5H)-trione to improve its pharmacokinetic properties

Combination of chiral linkers with thiophenecarboximidamide heads to improve the selectivity of inhibitors of neuronal nitric oxide synthase

nNOS inhibition during profound asphyxia reduces seizure burden and improves survival of striatal phenotypic neurons in preterm fetal sheep

Development and characterization of 3-(benzylsulfonamido)benzamides as potent and selective SIRT2 inhibitors

Corrigendum to “Substituted pyrazolones require N2 hydrogen bond donating ability to protect against cytotoxicity from protein aggregation of mutant superoxide dismutase 1” [Bioorg. Med. Chem. Lett. 22 (2012) 6647–6650]

Partial neuroprotection by nNOS inhibition during profound asphyxia in preterm fetal sheep

Chiral linkers to improve selectivity of double-headed neuronal nitric oxide synthase inhibitors

Two continuous coupled assays for ornithine-δ-aminotransferase

In search of potent and selective inhibitors of neuronal nitric oxide synthase with more simple structures

Antagonism of L-type Ca2+ channels CaV1.3 and CaV1.2 by 1,4-dihydropyrimidines and 4H-pyrans as dihydropyridine mimics

Cyclopropyl- and methyl-containing inhibitors of neuronal nitric oxide synthase

Probing the steric requirements of the γ-aminobutyric acid aminotransferase active site with fluorinated analogues of vigabatrin

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