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A series of indole tetrahydropyridine and indole cyclohexenylamines was prepared, and their binding affinities at the human serotonin transporter (SERT) were determined. In particular, a nitrile substituent at the C5 position of the indole ring gave potent SERT activity. The stereochemistry of the N,N-dimethylamine substituent was determined for the most potent indole cyclohexenylamine, 6a. The enantiomers of 6a were energy minimized and compared to other conformationally restricted SSRIs. Compound 6a was found to give a dose-response similar to the SSRI fluoxetine in microdialysis studies in rats.

Novel C-5 substituted pyrrolotriazines were optimized for dual EGFR and HER2 protein tyrosine kinase inhibition. The lead compound exhibited promising oral efficacy in both EGFR and HER2 driven human tumor xenograft models. It is hypothesized that its C-5 morpholine side chain binds in the ribose phosphate portion of the ATP binding pocket.

Bioisosteric replacement studies led to the identification of N -(1-benzo[1,3]dioxol-5-yl-ethyl)-3-(2-chloro-phenyl)-acrylamide (( S )- 3 ) as a highly potent KCNQ2 opener, and 3-(2,6-difluoro-phenyl)- N -[1-(2,3-dihydro-benzofuran-5-yl)-ethyl]-acrylamide (( S )- 4 ), and N -[1-(2,3-dihydro-1 H -indol-5-yl)-ethyl]-3-(2-fluoro-phenyl)-acrylamide (( S )- 5 ) as highly efficacious KCNQ2 openers. In contrast, their respective R enantiomers showed significantly less or no appreciable KCNQ2 opener activity even at the highest concentration tested (10 μM). Because of its high potency and moderate efficacy as well as its convenient synthesis, (±)- 3 was selected as a reference compound for analyzing efficacies of KCNQ openers in electrophysiology studies. Compounds ( S )- 4 and ( S )- 5 demonstrated significant activity in reducing neuronal hyperexcitability in rat hippocampal slices. The synthesis and the KCNQ2 opener activity of these acrylamides are described.

A new class of acrylamides was synthesized, and the effects of these analogues on outward potassium current were evaluated by using two electrode voltage clamp recordings from Xenopus laevis oocytes expressing cloned mKCNQ2 channels. SAR studies indicated that the pharmacophore of the acrylamide series includes the (S) absolute configuration at the (1-phenyl)ethyl moiety and the alpha,beta-unsaturated acrylamide functionality with a free NH. This study identified (S)-N-[1-(3-morpholin-4-yl-phenyl)-ethyl]-3-phenyl-acrylamide ((S)-1) and (S)-N-[1-(4-fluoro-3-morpholin-4-yl-phenyl)-ethyl]-3-(4-fluoro-phenyl)-acrylamide ((S)-2) as KCNQ2 openers for further electrophysiological evaluations. These two acrylamides demonstrated significant activity in the cortical spreading depression model of migraine as we reported previously.

A series of potent inhibitors of P-selectin as potential anti-inflammatory agents is reported. These compounds are derivatives of galactocerebrosides bearing a malonate side chain in positions 2 and 3 of the galactose moiety. Based on the binding mode of sialyl Lewis X, the two acidic groups of the malonate are designed to form ionic interactions with two important lysines in the active site of P-selectin, Lys113 and Lys111. On the other hand, the 4- and 6-hydroxy groups on the galactose ring are arranged to chelate the calcium ion in the P-selectin active site. The synthesis and the biological activity of this series of compounds are described. Lead compounds having a greater potency than sialyl Lewis X are identified.

A number of N-substituted 1-(5-fluoro-2-pyrimidinyl)piperazine derivatives were prepared and evaluated for binding to sigma and serotonin 5-HT 1A and 5-HT 2 receptor subtypes as well as for their protection against nitrogen anoxia-induced lethality in rats. Although various compounds exhibited good binding affinity and/or anti-anoxic effects, there was no obvious correlation between their receptor binding and in vivo effects.

A number of N-substituted 1-(5-fluoro-2-pyrimidinyl)piperazine derivatives were prepared and evaluated for binding to sigma and serotonin 5-HT 1A and 5-HT 2 receptor subtypes as well as for their protection against nitrogen anoxia-induced lethality in rats. Although various compounds exhibited good binding affinity and/or anti-anoxic effects, there was no obvious correlation between their receptor binding and in vivo effects.

A series of 1-(pyrimidin-2-yl)piperazine derivatives were prepared and evaluated in receptor binding assays and in in vivo behavioral paradigms as potential atypical antipsychotic agents. Compound 16 (BMS 181100 (formerly BMY 14802)) emerged as the lead compound from within the series on the basis of its good activity and duration of action in the inhibition of both conditioned avoidance responding and apomorphine-induced stereotopy in the rat. Compound 16 not only failed to induce catalepsy in the rat but was quite effective in reversing the cataleptic effect of neuroleptic agents, thus indicating a low propensity for causing extrapyramidal side effects. In comparison to reference antipsychotic agents, 16 appeared to be less sedating and was relatively weaker in causing muscle incoordination. The compound was essentially inactive in binding to dopamine D2 receptors and its chronic administration to rats did not result in dopamine receptor supersensitivity. It exhibited modest to weak affinity for 5-HT1A and alpha 1 receptors but was found to be a fairly potent ligand for sigma binding sites (IC50 vs (+)-[3H]-3-PPP = 112 nM). Although the resolved enantiomers of racemic 16 did not show dramatic differences from racemate or from each other in most tests, the R(+) enantiomer was up to 11-fold more potent than its antipode in binding to sigma sites. Several studies have indicated that 16 may be a limbic-selective agent which may modulate dopaminergic activity by an indirect mechanism. The compound has been selected for clinical evaluation in the treatment of psychosis.

In the initial stages of influenza virus infection, the hemagglutinin (HA) protein of influenza virus mediates both adsorption and penetration of the virus into the host cell. Recently, we identified and characterized BMY-27709 as an inhibitor of the H1 and H2 subtypes of influenza A virus that specifically inhibits the HA function necessary for virus-cell membrane fusion (G.-X. Luo, R. Colonno, and M. Krystal, Virology 226:66-76, 1996). Studies presented herein show that the inhibition is mediated through specific interaction with the HA protein. This binding represses the low-pH-induced conformational change of the HA protein which is a prerequisite for membrane fusion. In an attempt to define the binding pocket within the HA molecule, a number of drug-resistant viruses have been isolated and characterized. Sequence analyses of the HA gene of these drug-resistant viruses mapped amino acid changes responsible for drug resistance to a region located near the amino terminus of HA2. In addition, we have identified inactive analogs of BMY-27709 which are able to compete out the inhibitory activity of BMY-27709. This finding suggests that inhibition of the HA-mediated membrane fusion by this class of compounds is not solely the result of binding within the HA molecule but requires specific interactions.

Crystals of the phenylurethane derivative of a novel bicyclic lactone, C18H21NO8, have an orthorhombic unit cell of dimensionsa = 8.648(2),b = 11.041(7),c = 19.589(4) A, and belong to space groupP212121. The structure was solved by direct methods and was refined by the block diagonal approximation to a finalR value of 0.034 using 1035 reflections. The structure is made up of a six-membered lactone ring, in the boat conformation,cis-fused to a five-membered oxolane ring. The phenylurethane and the methoxy groups aretrans to each other, while the ethyl carboxylate group is attached in equatorial position.

1,4-Anhydro- d -glucitol has been used as a chiral template for the synthesis of 11-oxaprostaglandin F 2 α and F 2 β. Methodology was also developed to provide access to chiral, C -branched tetrahydrofuran derivatives.

Condensation of 1,6-N,O-carbonyl-3-N-ethoxycarbonyl-2,5-dideoxystreptamine (7) with 6-azido-2,3,4-tri-O-benzyl-6-deoxy-α-D-glucopyranosyl chloride by the Koenigs–Knorr reaction produced the α-glycoside 10. The cyclic carbamate of 10 was opened with ethanol in the presence of sodium ethoxide and the resulting 4-O-(6-azido-2,3,4-tri-O-benzyl-6-deoxy-α-D-glucopyranosyl)-N,N′-diethoxycarbonyl-2,5-dideoxystreptamiue (12) was glycosidated with 3-acetamido-2,4,6-tri-O-benzyl-3-deoxy-α-D-glucopyranosyl chloride (21) to give the α,α-diglycoside 22. Hydrogenation of the azido group and removal of the protective groups gave 5-deoxykanamycin A (25), an antibiotic with a potency about half that of kanamycin A.

The preparation of (4-tritylthio-2-azetidinon-l-yl)triphenylphosphoranylideneacetates from 4-acetoxyazetidin-2-one is described. They are easily converted to mercuric or silver mercaptides. These mercaptides are acylated with a wide variety of acylating agents and cyclized to 2-substituted penem-3-carboxylates.

The preparation of (4-tritylthio-2-azetidinon-l-yl)triphenylphosphoranylideneacetates from 4-acetoxyazetidin-2-one is described. They are easily converted to mercuric or silver mercaptides. These mercaptides are acylated with a wide variety of acylating agents and cyclized to 2-substituted penem-3-carboxylates.

Condensation of 1,6-N,O-carbonyl-3-N-ethoxycarbonyl-2,5-dideoxystreptamine (7) with 6-azido-2,3,4-tri-O-benzyl-6-deoxy-α-D-glucopyranosyl chloride by the Koenigs–Knorr reaction produced the α-glycoside 10. The cyclic carbamate of 10 was opened with ethanol in the presence of sodium ethoxide and the resulting 4-O-(6-azido-2,3,4-tri-O-benzyl-6-deoxy-α-D-glucopyranosyl)-N,N′-diethoxycarbonyl-2,5-dideoxystreptamiue (12) was glycosidated with 3-acetamido-2,4,6-tri-O-benzyl-3-deoxy-α-D-glucopyranosyl chloride (21) to give the α,α-diglycoside 22. Hydrogenation of the azido group and removal of the protective groups gave 5-deoxykanamycin A (25), an antibiotic with a potency about half that of kanamycin A.