Search

Starting from a naphthol-based lead series with low oral bioavailability, we have identified potent TRPV1 antagonists with oral bioavailability in rats. These compounds emerged from SAR studies aimed at replacing the lead's phenol structure whilst maintaining potency. Compound rac-6a is an orally available TRPV1 antagonist with single-digit nanomolar activity. The enantiomers show a low eudismic ratio at the receptor level. more...

We have identified naphthol derivatives as inhibitors of the vanilloid receptor TRPV1 by high throughput screening. The initial lead showed high clearance in rats and has been optimized by enhancing the acidity of the phenol group. Compound 6b has reduced clearance, improved potency and is active in rat cystometry models of urinary incontinence after intravenous administration. more...

A series of 2-amino-3-cyano-4-alkyl-6-(2-hydroxyphenyl)pyridine derivatives was synthesized and evaluated as IkappaB kinase beta (IKK-beta) inhibitors. Substitution of an aminoalkyl group for the aromatic group at the 4-position on the core pyridine ring resulted in a marked increase in both kinase enzyme and cellular potencies, and provided potent IKK-beta inhibitors with IC(50) values of below 100 nM. more...

A series of 2-amino-3-cyano-4-alkyl-6-(2-hydroxyphenyl)pyridine derivatives was synthesized and evaluated as I kappaB kinase beta (IKK-beta) inhibitors. Modification of a novel IKK-beta inhibitor 1 (IKK-beta IC(50)=1500 nM, Cell IC(50)=8000 nM) at the 4-phenyl ring and 6-phenol group on the pyridine core ring resulted in a marked increased in biological activities. An optimized compound, 2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-piperidin-4-yl nicotinonitrile, exhibited excellent in vitro profiles (IKK-beta IC(50)=8.5 nM, Cell IC(50)=60 nM) and a strong oral efficacy in in vivo anti-inflammatory assays (significant effects at 1mg/kg, po in arachidonic acid-induced ear edema model in mice). more...

IkappaB kinase beta (IKK-beta) is a serine-threonine protein kinase critically involved in the activation of the transcription factor Nuclear Factor kappa B (NF-kappaB) in response to various inflammatory stimuli. We have identified a small molecule inhibitor of IKK-beta. Optimization of the lead compound resulted in improvements in both in vitro and in vivo potency, and provided IKK-beta inhibitors exhibiting potent activity in an acute cytokine release model (LPS-induced TNFalpha). more...

A 5 kb DNA fragment encoding a hemolysin was cloned from the fish pathogenic bacterium Vibrio anguillarum using the cosmid vector charomid9-36. An open reading frame of the hemolysin gene (VAH1) was 2253 bp and corresponded to a protein of 751 amino acid residues. The deduced amino acid sequence of the VAH1 gene and the previously reported Vibrio cholerae EI Tor hemolysin, V. vulnificus cytolysin-hemolysin, Aeromonas hydrophila AHH1 hemolysin, and A. salmonicida ASH4 hemolysin showed a significant degree of sequence homology, and the overall amino acid identities were 57.3%, 25.8%, 46.2%, and 43.7%, respectively. DNA hybridization analysis under high-stringent conditions using VAH1 as a probe, demonstrated that VAH1 hybridized with 25 out of 28 strains of V. anguillarum including serotypes A to I, but did not hybridize with other species of Vibrio, A. hydrophila or A. salmonicida. The targeted DNA fragment of VAH1 was successfully amplified from V. anguillarum-infected fish tissues by PCR. more...

Hetero Diels-Alder reactions of optically active 3-(p-tolylsulfinyl)-2-furaldehyde with 1-methoxy-3-(trimethylsilyloxy)-buta-1,3-diene (Danishefsky's diene) in the presence of a Lewis acid has been examined. The reaction in the presence of 1.0 equiv. of Ln(OTf)3 (Ln = Yb, Nd and Sm) followed by acidic work-up produced in good yields (68–88%) the hetero Diels-Alder adduct with high diastereoisomeric excesses (93–98% d.e.'s), whereas in the presence of an NMR shift reagent, tris(2,2,6,6-tetramethyl-3,5-heptanedionate)europium [Eu(thd)3] the corresponding diastereoisomer was obtained as the major adduct in excellent yield with 77% d.e. more...

On the basis of the acetylcholine inhalation test performed in 45 patients who had atopic dermatitis, it appears that patients with a history of bronchial asthma (Group I), patients with a suggestive history of bronchial asthma (Group II), and nearly half of nonasthmatic patients with a family history of bronchial asthma (Group III) show respiratory thresholds to acetylcholine, ranging from 98 to 1,563 μg, as low as those of asthmatic patients. On the other hand, the rest of Group III and all of the patients with neither personal nor family history of bronchial asthma (Group IV) show values, from 1,563 to 25,000 μg, as high as those of healthy subjects. The patients in Group III with a lower value may be regarded as latent asthmatics. Thus, the patients with atopic dermatitis can clearly be divided into two groups, namely, (1) those with and (2) those without a predisposition to bronchial asthma. Consequently, it is reasonable to consider that atopic dermatitis and bronchial asthma are not based on a single predisposition controlled by the same gene, but rather on different predispositions controlled by separate genes. Their close genetic relationship might be more complicated than it was previously reported to be. more...