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Kelder, J.; Grootenhuis, Peter D. J.; Bayada, Denis M.; Delbressine, L. P. C.; Ploemen, J.H.T.M.

doi:10.1023/a:1015040217741

Cited by 724 publications

(264 citation statements)

References 7 publications

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“…In fact, even though 140 Å 2 is the highest PSA value permitted for BBB penetration according to the now accepted criteria of druglikeness, 40,41) orally administered drugs with PSA Ͼ120 Å 2 are in general hardly absorbed by the passive transcellular route. [39][40][41] In contrast, drugs with a low PSA value (Ͻ60 Å 2 ) could be almost completely absorbed. Most of the compounds reported herein have PSA values Ն120 Å 2 with the only exceptions being derivatives 4 and 8 whose PSA values are however Ͼ60 Å 2 .…”

Section: Resultsmentioning

confidence: 99%

Pharmacological Characterization of Some Selected 4,5-Dihydro-4-oxo-1,2,4-triazolo[1,5-a]quinoxaline-2-carboxylates and 3-Hydroxyquinazoline-2,4-diones as (S)-2-Amino-3-(3-hydroxy-5-methylisoxazol-4-yl)-propionic Acid Receptor Antagonists

Catarzi

Lenzi

Colotta

et al. 2010

CHEMICAL & PHARMACEUTICAL BULLETIN

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Glutamate (Glu), the primary excitatory neurotransmitter in the mammalian central nervous system (CNS), plays pivotal roles in regulating neuronal activity in many physiological processes such as synaptic plasticity, learning and memory.1,2) Glu is also important for neuronal migration, differentiation, and for the establishment or elimination of synapses in the developing brain. [3][4][5] The machinery for signal input consists of glutamate receptors including G-protein coupled receptors (metabotropic receptors or mGluRs), and ligandgated ion channels (ionotropic receptors or iGluRs).6) The latter are divided into three distinct subtypes, namely (S)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)-propionic acid (AMPA), kainate (KA), and N-methyl-D-aspartic acid (NMDA) receptors, according to the synthetic agonist that activates them preferentially. The NMDA ion-channel complex possesses different binding sites including the glycine coagonist binding site (Gly/NMDA). 7) Based on molecular cloning seven subunits (NR1, NR2A-D, and NR3A-B) for the NMDA receptor, four (GluR1-4) for the AMPA and five (GluR5-7, KA1-2) for the KA receptor have been identified. [8][9][10] There is considerable evidence that GluRs are involved in many neurological processes in the diseased CNS. In fact, glutamatergic hyperactivity can induce an increase of intracellular free Ca 2ϩ levels and cause collapse of mitochondrial function, potentially leading to secondary neurotoxic events and cell death. These processes are implicated in a large number of acute and chronic neurodegenerative pathologies such as cerebral ischemia, 11) epilepsy, 2) Alzheimer's 12,13) and Parkinson's 14) diseases, and amyotrophic lateral sclerosis (ALS).15) A large body of data indicate that glutamatergic neurotransmission is involved in nociceptive reflexes at the spinal cord level. 16)Several studies indicated that many compounds acting as iGluR antagonists have beneficial effects against neurodegenerative disorders.17-20) These findings gave life to extensive investigations of AMPA receptor antagonists belonging to the classical quinoxalinedione and heterocyclic-fused quinoxalinedione series most of which are endowed with interesting pharmacological profiles.21)The success of AMPA receptor antagonists over other well pharmacologically-characterized iGluR antagonists is probably due to their greater clinical potential. In fact, most of the NMDA receptor antagonists, though showing interesting neuroprotective activity in many animal models of cerebral ischemia, also produced important adverse effects including psychotomimetic activity. 22)In the near future, the emerging clinical application for competitive AMPA receptor antagonists will probably be as neuroprotectants in neurodegenerative diseases, such as epileptic conditions, [23][24][25][26] as an alternative to current therapies. In fact, most of the currently used antiepileptic drugs (AEDs) produce adverse effects, and show to be ineffective in refractory epilepsy. 27) As approximately 0.5-2% of the world popul...

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Section: Resultsmentioning

confidence: 99%

Pharmacological Characterization of Some Selected 4,5-Dihydro-4-oxo-1,2,4-triazolo[1,5-a]quinoxaline-2-carboxylates and 3-Hydroxyquinazoline-2,4-diones as (S)-2-Amino-3-(3-hydroxy-5-methylisoxazol-4-yl)-propionic Acid Receptor Antagonists

Catarzi

Lenzi

Colotta

et al. 2010

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…It is possible that larger or longer treatment regimens could achieve cure of stage 1 disease by oral delivery, but this would need to be investigated further. The lack of CNS penetration also is probably due to the physicochemical properties of the molecule (38), preventing passive diffusion across the blood-brain barrier.…”

Section: Discussionmentioning

confidence: 99%

Characterization of a Melamino Nitroheterocycle as a Potential Lead for the Treatment of Human African Trypanosomiasis

Giordani

Buschini

Baliani

et al. 2014

Antimicrob Agents Chemother

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dThis paper reports an evaluation of a melamino nitroheterocycle, a potential lead for further development as an agent against human African trypanosomiasis (HAT). Studies on its efficacy, physicochemical and biopharmaceutical properties, and potential for toxicity are described. The compound previously had been shown to possess exceptional activity against Trypanosoma brucei in in vitro assays comparable to that of melarsoprol. Here, we demonstrate that the compound also was curative in the stringent acute mouse model T. brucei rhodesiense STIB 900 when given intraperitoneally at 40 mg/kg of body weight. Nevertheless, activity was only moderate when the oral route was used, and no cure was obtained when the compound was tested in a stage 2 rodent model of infection. Genotoxic profiling revealed that the compound induces DNA damage by a mechanism apparently independent from nitroreduction and involving the introduction of base pair substitutions (Ames test), possibly caused by oxidative damage of the DNA (comet test). No significant genotoxicity was observed at the chromosome level (micronucleus assay). The lack of suitable properties for oral and central nervous system uptake and the genotoxic liabilities prevent the progression of this melamine nitroheterocycle as a drug candidate for HAT. Further modification of the compound is required to improve the pharmacokinetic properties of the molecule and to separate the trypanocidal activity from the toxic potential.

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“…Literature review suggests that TPSA is a measure of a molecule's hydrogen bonding capacity and its value should not exceed certain limit if the compound is intended to be CNS active. Two differing limits have been proposed: van de Waterbeemed et al 7 suggest a limit of 90 A 2 , where, Kelder et al 8 suggest 60-70 A 2 .…”

Section: Computation Of Physiochemical Propertiesmentioning

confidence: 99%

Synthesis, Computational Studies and Preliminary Pharmacological Evaluation of New Arylpiperazines

Kumar

Wahi

Singh

2010

Journal of Chemistry

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A series of novel arylpiperazines were synthesized and the target compounds evaluated for atypical antipsychotic activity in apomorphine induced climbing behavior (D 2 antagonism), 5-HTP induced head twitches (5-HT 2A antagonism) and catalepsy studies in albino mice. The physicochemical similarity of the target compounds with respect to standard drugs clozapine, ketanserine and risperidone was assessed by calculating from a set of physiochemical properties using software programs. The test compounds (3a-j) demonstrated good similarity values with respect to the standard drugs. Among them, compound 3d has emerged as an important lead compound showing potential atypical antipsychotic like profile.

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Abstract: The polar molecular surface area is a dominating determinant for oral absorption and brain penetration of drugs that are transported by the transcellular route. This property should be considered in the early phase of drug screening.

Cited by 724 publications

References 7 publications

Pharmacological Characterization of Some Selected 4,5-Dihydro-4-oxo-1,2,4-triazolo[1,5-a]quinoxaline-2-carboxylates and 3-Hydroxyquinazoline-2,4-diones as (S)-2-Amino-3-(3-hydroxy-5-methylisoxazol-4-yl)-propionic Acid Receptor Antagonists

Pharmacological Characterization of Some Selected 4,5-Dihydro-4-oxo-1,2,4-triazolo[1,5-a]quinoxaline-2-carboxylates and 3-Hydroxyquinazoline-2,4-diones as (S)-2-Amino-3-(3-hydroxy-5-methylisoxazol-4-yl)-propionic Acid Receptor Antagonists

Characterization of a Melamino Nitroheterocycle as a Potential Lead for the Treatment of Human African Trypanosomiasis

Synthesis, Computational Studies and Preliminary Pharmacological Evaluation of New Arylpiperazines

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