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Extensive SAR studies in our benzylpyrazole series of CCR5 antagonists have shown that both lipophilic and hydrophilic substituents on the phenyl of the benzyl group increase antiviral potency. However, improvements in pharmacokinetic profiles were generally only observed with more lipophilic substitutions. 4-Biphenyl (51) performed the best in this regard. Highly lipophilic substituents impart undesirable ion channel activity to these CCR5 antagonists. Alkoxy substituents provide a good balance of antiviral activity, pharmacokinetic parameters, and selectivity. Compounds 42b and 42d, containing a 3,4-dimethoxy substituent, are considered the most promising improvements over parent compounds 9. They demonstrate improved antiviral activity while retaining good pharmacokinetic profile and selectivity.

New strategies for the synthesis of (trialkylsilyl)vinylketenes (“TAS-vinylketenes”) are described based on the photochemical Wolff rearrangement of α‘-silyl-α‘-diazo-α,β-unsaturated ketones and the 4π electrocyclic ring opening of cyclobutenones. These remarkably robust vinylketenes undergo highly regioselective [4 + 2] cycloadditions with reactive olefinic and acetylenic dienophiles to produce highly substituted cyclohexenones and phenols in which the ketene carbonyl dominates in controlling the regiochemical course of the reaction. The stereochemical course of these cycloadditions follows the Alder endo rule, as illustrated in the reaction of nitropropene with TAS-vinylketene 22.

New strategies for the synthesis of (trialkylsilyl)vinylketenes (“TAS-vinylketenes”) are described based on the photochemical Wolff rearrangement of α‘-silyl-α‘-diazo-α,β-unsaturated ketones and the 4π electrocyclic ring opening of cyclobutenones. These remarkably robust vinylketenes undergo highly regioselective [4 + 2] cycloadditions with reactive olefinic and acetylenic dienophiles to produce highly substituted cyclohexenones and phenols in which the ketene carbonyl dominates in controlling the regiochemical course of the reaction. The stereochemical course of these cycloadditions follows the Alder endo rule, as illustrated in the reaction of nitropropene with TAS-vinylketene 22.

A photochemical aromatic annulation strategy provides efficient synthetic routes to the diterpenoid quinones (+)-danshexinkun A, danshexinkun B, danshexinkun C, (−)-dihydrotanshinone I, and tanshinone I.

Structure-activity relationship studies directed toward the optimization of (2S)-2-(3-chlorophenyl)-1-[N-(methyl)-N-(phenylsulfonyl)amino]-4-[4-(substituted)piperidin-1-yl]butanes as CCR5 antagonists resulted in the synthesis of the spiro-indanone derivative 8c (IC50=5 nM). These and previous results are summarized in a proposed pharmacophore model for this class of CCR5 antagonist.