High throughput screening using the recombinant human TRPV1 receptor was used to identify a series of pyridinylpiperazine ureas (3) as TRPV1 vanilloid receptor ligands. Exploration of the structure-activity relationships by parallel synthesis identified the essential pharmacophoric elements for antagonism that permitted further optimization via targeted synthesis to provide a potent orally bioavailable and selective TRPV1 modulator 41 active in several in vivo models.

Oligonucleotides containing thymine and cytosine (or 5-methylcytosine) bases are known to bind to specific homopurine sequences in double-stranded DNA by means of T.AT and C+.GC base triplets. Cytosine in the third strand of such triple helices can be completely replaced by 7,8-dihydro-8-oxoadenine a base which should not require protonation to form base triplets. Experiments using native PAGE and inhibition of triplex-directed photo-cross-linking demonstrate that triplexes with 7,8-dihydro-8-oxoadenine in the third strand are as stable at pH 6.0 as triplexes with 5-methylcytosine. The stability of triplexes with 7,8-dihydro-8-oxoadenine, unlike those with 5-methylcytosine, is not substantially diminished upon raising the pH to 7.4. Surprisingly, triplex formation with an oligonucleotide containing only thymine and 7,8-dihydro-8-oxoadenine was not associated with significant hypochromicity and could not be detected in conventional thermal denaturation experiments.

Imidazoles bearing vinyl and aryl substitution in the 4position can be prepared using palladium-catalyzed cross-coupling reactions of l-tritylimidazol-4-yltin and -zinc reagents in 67-80% yield. Importantly, these coupling methods appear to be general for aryl and vinyl bromides, iodides, and triflates.

A series of title compounds of type (I), (II) and (III) is prepared as potent antagonists of human vanilloid receptor 1 (VR1). The structure-activity relationships of the series are discussed. -(JETTER, M. C.; YOUNGMAN, M. A.; MCNALLY, J. J.; ZHANG, S.-P.; DUBIN, A. E.; NASSER, N.; DAX*, S. L.; Bioorg.

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