ABSTRACT
The alleged "madness" of the Anglo-Indian prince known as Dyce Sombre (1808-1851) has been attributed to anti-Asian prejudice, biased observations, and insensitivity to ethno-cultural variations in behavior. However, whereas all these factors may have contributed to misdiagnosis and mistreatment, there is compelling evidence pointing to an "organic" explanation for Dyce Sombre's aberrant behavior. We posit that the interaction of drug toxicity and possible central nervous system infection were primarily responsible for Dyce Sombre's clinical symptoms. The case provides an important lesson for modern-day psychiatrists confronting patients from other cultures who may also have underlying neuropsychiatric disorders.
ABSTRACT
A series of novel biphenyl pyrazole dicarboxamides were identified as potential sodium channel blockers for treatment of neuropathic pain. Compound 20 had outstanding efficacy in the Chung rat spinal nerve ligation (SNL) model of neuropathic pain.
Subject(s)
Biphenyl Compounds/chemistry , Neuralgia/drug therapy , Pyrazoles/chemistry , Sodium Channel Blockers/chemistry , Sodium Channels/chemistry , Animals , Biphenyl Compounds/chemical synthesis , Biphenyl Compounds/therapeutic use , Dogs , Drug Evaluation, Preclinical , Humans , Mice , Microsomes, Liver/metabolism , Motor Activity/drug effects , Pyrazoles/pharmacokinetics , Pyrazoles/therapeutic use , Rats , Sodium Channel Blockers/pharmacokinetics , Sodium Channel Blockers/therapeutic use , Sodium Channels/metabolismABSTRACT
Voltage-gated sodium channels have been shown to play a critical role in neuropathic pain. A series of low molecular weight biaryl substituted pyrazole carboxamides were identified with good in-vitro potency and in-vivo efficacy. Compound 26, a Nav1.7 blocker has excellent efficacy in the Chung model of neuropathic pain.
Subject(s)
Neuralgia/drug therapy , Pyrazoles/chemistry , Pyrazoles/therapeutic use , Sodium Channel Blockers/chemistry , Sodium Channel Blockers/therapeutic use , Sodium Channels/metabolism , Animals , Dogs , Haplorhini , Humans , Microsomes, Liver/metabolism , NAV1.7 Voltage-Gated Sodium Channel , Pyrazoles/pharmacokinetics , Pyrazoles/pharmacology , Rats , Sodium Channel Blockers/pharmacokinetics , Sodium Channel Blockers/pharmacology , Structure-Activity RelationshipABSTRACT
Voltage-gated sodium channels have been shown to play a critical role in neuropathic pain. With a goal to develop potent peripherally active sodium channel blockers, a series of low molecular weight biaryl substituted imidazoles, oxazoles, and thiazole carboxamides were identified with good in vitro and in vivo potency.
Subject(s)
Neuralgia/drug therapy , Oxazoles/therapeutic use , Sodium Channel Blockers/therapeutic use , Sodium Channels/metabolism , Thiazoles/therapeutic use , Animals , Dogs , Humans , Imidazoles/chemistry , Imidazoles/metabolism , Imidazoles/pharmacology , Imidazoles/therapeutic use , Microsomes, Liver/metabolism , NAV1.7 Voltage-Gated Sodium Channel , Oxazoles/chemistry , Oxazoles/metabolism , Oxazoles/pharmacology , Rats , Sodium Channel Blockers/chemistry , Sodium Channel Blockers/metabolism , Sodium Channel Blockers/pharmacology , Thiazoles/chemistry , Thiazoles/metabolism , Thiazoles/pharmacologyABSTRACT
Nodulisporic acid A (1) is a structurally complex fungal metabolite that exhibits systemic efficacy against fleas via modulation of an invertebrate specific glutamate-gated ion channel. In order to identify a nodulisporamide suitable for monthly oral dosing in dogs, a library of 335 nodulisporamides was examined in an artificial flea feeding system for intrinsic systemic potency as well as in a mouse/bedbug assay for systemic efficacy and safety. A cohort of 66 nodulisporamides were selected for evaluation in a dog/flea model; pharmacokinetic analysis correlated plasma levels with flea efficacy. These efforts resulted in the identification of the development candidate N-tert-butyl nodulisporamide (3) as a potent and efficacious once monthly oral agent for the control of fleas and ticks on dogs and cats which was directly compared to the topical agents fipronil and imidacloprid, with favorable results obtained. Multidose studies over 3 months confirmed the in vivo ectoparasiticidal efficacy and established that 3 lacked overt mammalian toxicity. Tissue distribution studies in mice using [(14)C]-labeled 3 indicate that adipose beds serve as ligand depots, contributing to the long terminal half-lives of these compounds.
Subject(s)
Insect Control , Insecticides , Siphonaptera , Ticks , Adipose Tissue/metabolism , Administration, Oral , Animals , Cats , Dogs , Female , Indole Alkaloids/chemical synthesis , Indole Alkaloids/pharmacokinetics , Indole Alkaloids/pharmacology , Indoles , Insecticides/administration & dosage , Insecticides/chemical synthesis , Male , Mice , Tissue DistributionABSTRACT
A series of 3-amino-1,5-benzodiazepinones were synthesized and evaluated as potential sodium channel blockers in a functional, membrane potential-based assay. One member of this series displayed subnanomolar, state-dependent sodium channel block, and was orally efficacious in a mouse model of epilepsy.
Subject(s)
Anticonvulsants/pharmacology , Benzodiazepinones/pharmacology , Epilepsy/drug therapy , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , Sodium Channel Blockers/pharmacology , Animals , Anticonvulsants/chemical synthesis , Anticonvulsants/pharmacokinetics , Benzodiazepinones/chemical synthesis , Benzodiazepinones/pharmacokinetics , Electrophysiology , Electroshock , Epilepsy/metabolism , Ether-A-Go-Go Potassium Channels/metabolism , Fluorescence Resonance Energy Transfer , Humans , Mice , Molecular Structure , Rats , Sodium Channel Blockers/chemical synthesis , Sodium Channel Blockers/pharmacokineticsABSTRACT
A series of beta-aminoamides bearing triazolopiperazines have been discovered as potent, selective, and orally active dipeptidyl peptidase IV (DPP-4) inhibitors by extensive structure-activity relationship (SAR) studies around the triazolopiperazine moiety. Among these, compound 34b with excellent in vitro potency (IC50 = 4.3 nM) against DPP-4, high selectivity over other enzymes, and good pharmacokinetic profiles exhibited pronounced in vivo efficacy in an oral glucose tolerance test (OGTT) in lean mice. On the basis of these properties, compound 34b has been profiled in detail. Further refinement of the triazolopiperazines resulted in the discovery of a series of extremely potent compounds with subnanomolar activity against DPP-4 (42b- 49b), that is, 4-fluorobenzyl-substituted compound 46b, which is notable for its superior potency (IC50 = 0.18 nM). X-ray crystal structure determination of compounds 34b and 46b in complex with DPP-4 enzyme revealed that (R)-stereochemistry at the 8-position of triazolopiperazines is strongly preferred over (S) with respect to DPP-4 inhibition.
Subject(s)
Amides/chemical synthesis , Dipeptidyl-Peptidase IV Inhibitors , Piperazines/chemical synthesis , Pyrazines/chemical synthesis , Triazoles/chemical synthesis , Amides/pharmacokinetics , Amides/pharmacology , Animals , Crystallography, X-Ray , Dipeptidyl Peptidase 4/chemistry , Dogs , Glucose Tolerance Test , Haplorhini , Humans , Male , Mice , Mice, Inbred C57BL , Piperazines/pharmacokinetics , Piperazines/pharmacology , Pyrazines/pharmacokinetics , Pyrazines/pharmacology , Rats , Stereoisomerism , Structure-Activity Relationship , Triazoles/pharmacokinetics , Triazoles/pharmacologyABSTRACT
A simple and efficient method for the preparation of pyrimidine 2'-O-hydroxyethoxymethylribonucleosides and 2'-O-hydroxypropoxymethylribonucleosides has been developed. These modified nucleosides were incorporated into oligoribonucleotides, which were shown to form stable RNA/RNA duplexes. The effect of 2' -O-modification in the antisense and sense strands of small interference RNA was evaluated in multi-drug resistant NIH 3T3 cells.
Subject(s)
Oligoribonucleotides/chemistry , Pyrimidines/chemistry , RNA/chemistry , Ribonucleosides/chemical synthesis , Ribonucleosides/chemistryABSTRACT
A series of benzodiazepines and benzazepinones were synthesized and evaluated as potential sodium channel blockers in a functional, membrane potential-based assay. One member of the benzazepinone series, compound 47, displayed potent, state-dependent block of hNa(v)1.7, and was orally efficacious in a rat model of neuropathic pain.
Subject(s)
Heterocyclic Compounds, 3-Ring/chemistry , Heterocyclic Compounds, 3-Ring/therapeutic use , Pain/drug therapy , Sodium Channel Blockers/classification , Sodium Channel Blockers/pharmacology , Sodium Channels/metabolism , Animals , Heterocyclic Compounds, 3-Ring/administration & dosage , Heterocyclic Compounds, 3-Ring/pharmacology , Molecular Structure , NAV1.7 Voltage-Gated Sodium Channel , Rats , Sodium Channel Blockers/chemistry , Sodium Channel Blockers/therapeutic use , Structure-Activity RelationshipABSTRACT
Novel cyclopentane-based 3-phenyl-1-hydroxypropyl compounds were evaluated for inhibitory activity against the peripheral nerve sodium channel Na(V)1.7 and off-target activity against the cardiac potassium channel hERG. The stereochemistry of the hydroxyl group and substitution on the phenyl rings with either fluorinated O-alkyl or alkyl groups were found to be critical for conferring potency against Na(V)1.7. A benchmark compound from this series displayed efficacy in rat models of inflammatory and neuropathic pain.
Subject(s)
Cyclopentanes/chemistry , Cyclopentanes/pharmacology , Sodium Channel Blockers/chemical synthesis , Sodium Channel Blockers/pharmacology , Sodium Channels/metabolism , Animals , Cyclopentanes/chemical synthesis , Cyclopentanes/pharmacokinetics , Ether-A-Go-Go Potassium Channels/metabolism , Humans , Inhibitory Concentration 50 , Molecular Structure , Rats , Sodium Channel Blockers/chemistry , Sodium Channel Blockers/pharmacokinetics , Structure-Activity RelationshipABSTRACT
PURPOSE: PAMAM G5 dendrimer (P) was conjugated to Tat peptide (T), a cell penetrating peptide, in search of an efficient cellular delivery vehicle for antisense and siRNA oligonucleotides. METHODS: PAMAM G5 dendrimer was reacted with 4,4-difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-s-indacene-3-propionic acid, sulfosuccinimidyl ester, sodium salt (BODIPY) for visualization to yield the conjugate BP. Bifunctional sulfosuccinimidyl 6-[alpha-methyl-alpha-(2-pyridyldithio)toluamido]hexanoate (sulfo-LC-SMPT) was then used to conjugate primary amino groups of BP to cysteine derivatized Tat peptide to give the designed conjugate, BPT. This conjugate was complexed with antisense and siRNA oligonucleotides designed to inhibit MDR1 gene expression. NIH 3T3 MDR cells were used for the evaluation of biological activity of the conjugate. RESULTS: Both antisense and siRNA readily formed complexes with the synthesized BPT, introduced into NIH 3T3 MDR cells, and primarily accumulated in intracellular vesicles. MDR1 gene expression was partially inhibited by the antisense-BPT complex and weakly inhibited by the siRNA-BPT complex when both were tested at nontoxic levels of dendrimer. Conjugation with Tat peptide did not improve the delivery efficiency of the dendrimer. CONCLUSIONS: Dendrimer-oligonucleotide complexes were moderately effective for delivery of antisense and only poorly effective for delivery of siRNA. Conjugation of the dendrimer with the Tat cell penetrating peptide failed to further enhance the effectiveness of the dendrimer.
Subject(s)
Dendrimers , Drug Delivery Systems , Gene Products, tat/chemistry , Oligonucleotides/administration & dosage , Polyamines/chemistry , RNA, Antisense/administration & dosage , RNA, Small Interfering/administration & dosage , 3T3 Cells , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Animals , Boron Compounds , Cell Survival/drug effects , Chromatography, Gel , Fluorescent Dyes , Genes, MDR/genetics , Mice , Microscopy, Confocal , Ribonucleases/metabolismABSTRACT
Cholesterol modified mono-, di-, and tetrameric oligonucleotides were synthesized and hybridized with antisense oligonucleotides to study their incorporation in cationic liposomes together with the influence of this dendrimeric delivery system on biological activity. Electrostatic interactions seem to play the most important role during complexation with cationic lipids. This oligonucleotide formulation gives a small but significant increase in the inhibition of P-glycoprotein expression in a cellular system.
Subject(s)
Cholesterol/chemistry , Lipids/chemistry , Oligonucleotides, Antisense/administration & dosage , 3T3 Cells , Animals , Cations , Fluorescence Resonance Energy Transfer , Magnetic Resonance Spectroscopy , Mass Spectrometry , Mice , Oligonucleotides, Antisense/chemistryABSTRACT
A new series of voltage-gated sodium channel blockers with potential for treatment of chronic pain is reported. Systematic structure-activity relationship studies, starting with compound 1, led to identification of potent analogs that displayed use-dependent block of sodium channels, were efficacious in pain models in vivo, and most importantly, were devoid of activity against the cardiac potassium channel hERG.
Subject(s)
Pain/drug therapy , Sodium Channel Blockers/therapeutic use , Chronic Disease , Humans , Molecular Conformation , Molecular Probes , Sodium Channel Blockers/chemistryABSTRACT
A series of new voltage-gated sodium channel blockers were prepared based on the screening lead succinic diamide BPBTS. Replacement of the succinimide linker with the more rigid cyclic 1,2-trans-diamide linker was well tolerated. N-Methylation on the biphenylsulfonamide side of the amide moiety significantly reduced the clearance rate in rat pharmacokinetic studies.
Subject(s)
Amides/chemistry , Amides/pharmacology , Cyclopentanes/pharmacology , Pain/drug therapy , Sodium Channel Blockers/chemical synthesis , Administration, Oral , Amides/chemical synthesis , Amides/therapeutic use , Analgesics/chemical synthesis , Analgesics/pharmacology , Animals , Biphenyl Compounds/chemistry , Cyclopentanes/chemical synthesis , Cyclopentanes/therapeutic use , Ion Channel Gating/drug effects , Methylation , Mexiletine/pharmacology , Pain Measurement/drug effects , Rats , Sodium Channel Blockers/pharmacology , Sodium Channel Blockers/therapeutic use , Structure-Activity Relationship , Succinates/chemistry , Sulfonamides/chemistryABSTRACT
A novel series of beta-amino amides incorporating fused heterocycles, i.e., triazolopiperazines, were synthesized and evaluated as inhibitors of dipeptidyl peptidase IV (DPP-IV) for the treatment of type 2 diabetes. (2R)-4-Oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine (1) is a potent, orally active DPP-IV inhibitor (IC(50) = 18 nM) with excellent selectivity over other proline-selective peptidases, oral bioavailability in preclinical species, and in vivo efficacy in animal models. MK-0431, the phosphate salt of compound 1, was selected for development as a potential new treatment for type 2 diabetes.
Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Dipeptidyl Peptidase 4/drug effects , Enzyme Inhibitors/pharmacology , Hypoglycemic Agents/pharmacology , Pyrazines/chemistry , Pyrazines/pharmacology , Triazoles/chemistry , Triazoles/pharmacology , Administration, Oral , Animals , Binding Sites , Biochemistry/methods , Blood Glucose/analysis , Crystallography, X-Ray , Dipeptidyl Peptidase 4/chemistry , Dipeptidyl Peptidase 4/metabolism , Dogs , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical/methods , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacokinetics , Glucagon/blood , Glucagon/drug effects , Glucagon-Like Peptide 1 , Glucose Tolerance Test , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacokinetics , Mice , Mice, Inbred C57BL , Models, Molecular , Peptide Fragments/blood , Peptide Fragments/drug effects , Protein Conformation , Protein Precursors/blood , Protein Precursors/drug effects , Pyrazines/pharmacokinetics , Rats , Sitagliptin Phosphate , Structure-Activity Relationship , Triazoles/pharmacokineticsABSTRACT
Hexitol nucleic acids (HNAs) are nuclease resistant and provide strong hybridization to RNA. However, there is relatively little information on the biological properties of HNA antisense oligonucleotides. In this study, we compared the antisense effects of a chimeric HNA 'gapmer' oligonucleotide comprising a phosphorothioate central sequence flanked by 5' and 3' HNA sequences to conventional phosphorothioate oligonucleotides and to a 2'-O-methoxyethyl (2'-O-ME) phosphorothioate 'gapmer'. The antisense oligomers each targeted a sequence bracketing the start codon of the message of MDR1, a gene involved in multi-drug resistance in cancer cells. Antisense and control oligonucleotides were delivered to MDR1-expressing cells using transfection with the cationic lipid Lipofectamine 2000. The anti-MDR1 HNA gapmer was substantially more potent than a phosphorothioate oligonucleotide of the same sequence in reducing expression of P-glycoprotein, the MDR1 gene product. HNA and 2'-O-ME gapmers displayed similar potency, but a pure HNA antisense oligonucleotide (lacking the phosphorothioate 'gap') was ineffective, indicating that RNase H activity was likely required. Treatment with anti-MDR1 HNA gapmer resulted in increased cellular accumulation of the drug surrogate Rhodamine 123 that correlated well with the reduced cell surface expression of P-glycoprotein. Thus, HNA gapmers may provide a valuable additional tool for antisense-based investigations and therapeutic approaches.
Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/antagonists & inhibitors , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Oligonucleotides, Antisense/chemistry , Oligonucleotides, Antisense/pharmacology , ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Animals , Antineoplastic Agents/metabolism , Biological Transport/drug effects , Blotting, Western , Cell Line , Flow Cytometry , Fluorescent Dyes/metabolism , Gene Expression Regulation , Mice , NIH 3T3 Cells , Oligonucleotides, Antisense/metabolism , Rhodamine 123/metabolism , Sugar Alcohols/chemistry , Thionucleotides/chemistryABSTRACT
Antisense oligonucleotides were potentially very powerful tools to modulate gene expression. Progress in chemical modification of oligonucleotides to enhance the strength and stability of interaction, without loosing specificity, has made the antisense strategy very attractive for therapeutic manipulation of the gene expression. However, pharmacological applications of oligonucleotides have been hindered by the inability to effectively deliver these compounds to their sites of action within cells. In this study we evaluated a new concept for antisense delivery in cellular systems. We have shown that formation of a duplex between the active oligonucleotide (with a chemically modified backbone) and an easily degradable complementary oligodeoxynucleotide in the presence of Lipofectamine 2000 leads to better intracellular uptake and more significant pharmacological effect of the active oligonucleotide. To evaluate our approach we targeted the MDR1 gene, which coded for P-glycoprotein, a membrane ATPase associated with multi-drug resistance in tumor cells. The 2'-O-methyl gapmer antisense RNA (active component of the duplex) was complementary to a site flanking the AUG of the MDR1 message. Effective inhibition of P-glycoprotein expression was attained with sub-micromolar concentrations of duplexes under serum-replete conditions and was much stronger than with traditional single stranded antisense delivery. The results obtained suggested that double stranded delivery could provide a simple and effective means for enhancing cell uptake of pharmacologically active oligonucleotides.
Subject(s)
Drug Delivery Systems , Oligoribonucleotides, Antisense/administration & dosage , RNA, Double-Stranded/administration & dosage , 3T3 Cells , ATP Binding Cassette Transporter, Subfamily B, Member 1/antagonists & inhibitors , ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics , Animals , Gene Expression/drug effects , Humans , Mice , TransfectionABSTRACT
Aryldihydropyridazinones and aryldimethylpyrazolones with 2-benzyl vinylogous amide substituents have been identified as potent PDE3B subtype selective inhibitors. Dihydropyridazinone 8a (PDE3B IC(50)=0.19 nM, 3A IC(50)=1.3 nM) was selected for in vivo evaluation of lipolysis induction, metabolic rate increase, and cardiovascular effects.
Subject(s)
3',5'-Cyclic-AMP Phosphodiesterases/antagonists & inhibitors , Phosphodiesterase Inhibitors/chemical synthesis , Phosphodiesterase Inhibitors/pharmacology , Pyridazines/chemical synthesis , Cyclic Nucleotide Phosphodiesterases, Type 3 , Drug Design , Kinetics , Pyridazines/pharmacology , Structure-Activity Relationship , Vinyl Compounds/chemical synthesis , Vinyl Compounds/pharmacologyABSTRACT
Efficient routes to access the 2", 3", 4", and 6" registers of the nodulisporic acid (NsA) side chain are disclosed. A mild one-carbon, Ph(2)CdoublebondNCH(2)CtriplebondN mediated homologation of NsA's 3"-aldehyde permitted access to the 4"-register. Curtius reaction of NsA's 3"-acid yielded the corresponding 2"-aldehyde 4 from which the unnatural Delta(2",3")-olefin isomer 2b was obtained. In addition, Arndt-Eistert reactions of the parent NsA permitted a one-carbon homologation to the 6" register. These efforts identified new analogues with significant flea activity and illustrated the biological significance of unsaturation at the 1",2" register.
Subject(s)
Indoles/chemistry , Insecticides/chemical synthesis , Alkenes , Animals , Dose-Response Relationship, Drug , Indoles/pharmacology , Insecticides/pharmacology , Siphonaptera/drug effects , Structure-Activity RelationshipABSTRACT
A series of new, diene-modified nodulisporic acid analogues (2) bearing diverse functionality at the 3"- and 4"-sites was efficiently prepared from the 3"-aldehyde 3. Biological evaluation of these synthetic nodulisporic acid analogues for systemic flea efficacy identified potent compounds and further clarified the structural requirements for ectoparasite activity.