Discovery of 3-Hydroxymethyl-5-methylisoxazole

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Novel diamino derivatives of [1,2,4]triazolo[1,5-a][1,3,5]triazine as potent and selective adenosine A2a receptor antagonists

Piperazine derivatives of 2-furanyl[1,2,4]triazolo[1,5-a][1,3,5]triazine have recently been demonstrated to be potent and selective adenosine A 2a receptor antagonists with oral activity in rodent models of Parkinson’s disease. We have replaced the piperazinyl group with a variety of linear, monocyclic, and bicyclic diamines. Of these diamines, (R)-2-(aminomethyl)pyrrolidine is a particularly potent and selective replacement for the piperazinyl group. With this diamine component, we have been able to prepare numerous analogues with low nanomolar affinity toward the A2a receptor and good selectivity with respect to the A1 receptor (> 200-fold in some cases). Selected analogues from this series of [1,2,4]triazolo[1,5-a][1,3,5]triazine have now been shown to be orally active in the mouse catalepsy model.

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1,3,4-oxadiazolyl-phenoxyalkylisoxazoles and their use as antiviral agents

Compounds of the formula STR1 wherein: Y is an alkylene bridge of 3-9 carbon atoms; R’ is lower-alkyl or hydroxy-lower-alkyl or 1-5 carbon atoms; R1 and R2 are hydrogen, halogen, lower-alkyl, lower-alkoxy, nitro, lower-alkoxycarbonyl or trifluoromethyl; and R8 is hydrogen or lower-alkyl of 1-5 carbon atoms, with the proviso that when R8 is hydrogen R’ is hydroxy-lower-alkyl, are useful as antiviral agents, particularly against picornaviruses, including numerous strains of rhinovirus.

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COMPOUNDS AND THEIR METHODS OF USE

The present invention is directed to, in part, fused heteroaryl compounds and compositions useful for preventing and/or treating a disease or condition relating to aberrant function of a voltage-gated, sodium ion channel, for example, abnormal late/persistent sodium current. Methods of treating a disease or condition relating to aberrant function of a sodium ion channel including Dravet syndrome or epilepsy are also provided herein.

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SAR studies of C2 ethers of 2H-pyrano[2,3-d]pyrimidine-2,4,7(1H,3H)-triones as nicotinic acid receptor (NAR) agonist

Based on in house screening lead compound 1 for the NAR project, SAR studies have been focused on the modification of the C2 ethers of the pyrimidinedione core structure. In this effort, an unpredictable SAR trend was overcome in the alkyl ether and arylalkyl ether series to identify compound 24 with improved in vitro activity compared to nicotinic acid. More consistent and predictable SAR was achieved in the propargyl ether series. Lead compound 41 was identified with good in vitro and in vivo activity in rat, and much improved rat PK profile.

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Improving the nicotinic pharmacophore with a series of (isoxazole)methylene-1-azacyclic compounds: Synthesis, structure-activity relationship, and molecular modeling

A series of (isoxazole)methylene-1-azacyclic compounds was prepared. The compounds were tested for affinity to central nicotinic acetylcholine receptors (nAChRs) and central muscarinic receptors. The compounds covered a broad range of affinities for the nAChRs (IC50 = 0.32 to > 1000 nM), with selectivities for the nAChRs over the muscarinic receptors in the range of 3- 183. The high-affinity compound (Z)-26 (3-(4-methyl-5-isoxazolyl)methylene-1- azabicyclo[2.2.2]octane, IC50 = 3.2 nM) having only one energy minimum was used as the reference structure in a computational study. This ligand has enabled definition of an important distance parameter, and the existence of this parameter was supported by showing that other potent nicotinic ligands (for example, nicotine and epibatidine) fit the model.

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Pyrrolopyrimidines as therapeutic agents

Chemical compounds having structural formula I 1and physiologically acceptable salts and metabolites thereof, are inhibitors of serine/threonine and tyrosine kinase activity. Several of the kinases, whose activity is inhibited by these chemical compounds, are involved in immunologic, hyperproliferative, or angiogenic processes. Thus, these chemical compounds can ameliorate disease states where angiogenesis or endothelial cell hyperproliferation is a factor. These compounds can be used to treat cancer and hyper proliferative disorders, rheumatiod arthritis, disorders of the immune system, trasplant refections and imflammatory disorders.

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Synthesis and biological evaluation of novel 2,4-diaminoquinazoline derivatives as SMN2 promoter activators for the potential treatment of spinal muscular atrophy

Proximal spinal muscular atrophy (SMA) is an autosomal recessive disorder characterized by death of motor neurons in the spinal cord that is caused by deletion and/or mutation of the survival motor neuron gene (SMN1). Adjacent to SMN1 are a variable number of copies of the SMN2 gene. The two genes essentially differ by a single nucleotide, which causes the majority of the RNA transcripts from SMN2 to lack exon 7. Although both SMN1 and SMN2 encode the same Smn protein amino acid sequence, the loss of SMN1 and incorrect splicing of SMN2 have the consequence that Smn protein levels are insufficient for the survival of motor neurons. The therapeutic goal of our medicinal chemistry effort was to identify small-molecule activators of the SMN2 promoter that, by up-regulating gene transcription, would produce greater quantities of full-length Smn protein. Our initial medicinal chemistry effort explored a series of C5 substituted benzyl ether based 2,4-diaminoquinazoline derivatives that were found to be potent activators of the SMN2 promoter; however, inhibition of DHFR was shown to be an off-target activity that was linked to ATP depletion. We used a structure-guided approach to overcome DHFR inhibition while retaining SMN2 promoter activation. A lead compound 11a was identified as having high potency (EC50 = 4 nM) and 2.3-fold induction of the SMN2 promoter. Compound 11a possessed desirable pharmaceutical properties, including excellent brain exposure and long brain half-life following oral dosing to mice. The piperidine compound 11a up-regulated expression of the mouse SMN gene in NSC-34 cells, a mouse motor neuron hybrid cell line. In type 1 SMA patient fibroblasts, compound 11a induced Smn in a dose-dependent manner when analyzed by immunoblotting and increased the number of intranuclear particles called gems. The compound restored gems numbers in type I SMA patient fibroblasts to levels near unaffected genetic carriers of SMA.

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NEW ISOXAZOLYL ETHER DERIVATIVES AS GABA A ALPHA5 PAM

The invention provides novel c ompounds having the general formula (I) or (II) wherein R2, R3, R5, R99, W, Y and Z are as desc ribed herein, c ompositions including the c ompounds and methods of using the c ompounds.

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Design, Synthesis, and Biological Evaluation of Allosteric Effectors That Enhance CO Release from Carboxyhemoglobin

Carbon monoxide (CO) poisoning causes between 5,000-6,000 deaths per year in the US alone. The development of small molecule allosteric effectors of CO binding to hemoglobin (Hb) represents an important step toward making effective therapies for CO poisoning. To that end, we have found that the synthetic peptide IRL 2500 enhances CO release from COHb in air, but with concomitant hemolytic activity. We describe herein the design, synthesis, and biological evaluation of analogs of IRL 2500 that enhance the release of CO from COHb without hemolysis. These novel structures show improved aqueous solubility and reduced hemolytic activity and could lead the way to the development of small molecule therapeutics for the treatment of CO poisoning.

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Antibacterial monic acid derivatives

A compound of the formula (I) STR1 wherein R is a group STR2 R1 is hydrogen, phenyl, C1-20 alkyl, C2-8 alkenyl or C2-8 alkynyl each of which may optionally be substituted; or C3-7 cycloalkyl, X is a divalent group –Y–C=C–, and Y is oxygen or sulphur, have antibacterial and/or antimycoplasmal activity.

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