The serotonin/noradrenaline reuptake inhibitor rac-1- [2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]cyclohexan-1-ol (rac-venlafaxine, rac-1a) is in clinical use as an antidepressant. The silicon analogue, rac-1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]-1-silacyclohexan-1-ol (rac-sila-venlafaxine, rac-1b), was synthesized in multistep syntheses, starting from tetrachlorosilane or tetramethoxysilane. The corresponding 1-silacyclopentan-1-ol derivative rac-2 was prepared analogously. The sila-venlafaxine enantiomers (R)-1b and (S)-1b were obtained by resolution of rac-1b, using (+)-or (-)-10camphorsulfonic acid as the resolving agent. Compounds rac-1b, (R)-1b, (S)-1b, rac-1b‚HCl, (R)-1b‚ HCl, (S)-1b‚HCl, (R)-1b‚HBr, rac-2, and rac-2‚HCl were characterized by multinuclear NMR studies and elemental analyses, and rac-1b‚HCl, (R)-1b‚HBr, and rac-2 were additionally characterized by crystal structure analyses. Compounds rac-1a, rac-1b, rac-2, (R)-1a, (S)-1a, (R)-1b, and (S)-1b were tested as their hydrochlorides for their efficacy in serotonin, noradrenaline, and dopamine reuptake inhibition assays. Sila-substitution (C/Si switch) of compounds rac-1a, (R)-1a, and (S)-1a (f rac-1b, (R)-1b, (S)-1b) was found to dramatically influence their pharmacological selectivity profiles with respect to serotonin, noradrenaline, and dopamine reuptake inhibition. (R)-Sila-venlafaxine ((R)-1b) was identified to have a refined selectivity profile consistent with selective noradrenaline reuptake inhibition. Compounds with this profile may provide therapeutic benefit in the treatment of various nervous system disorders.

-5-quinoline carboxamide (SCH 351591) has been identified as a potent (IC 50 ϭ 58 nM) and highly selective type 4 phosphodiesterase (PDE4) inhibitor with oral bioactivity in several animal models of lung inflammation. N-(3,5-Dichloro-4-pyridinyl)-8-methoxy-2-(trifluoromethyl)-5-quinoline carboxamide (SCH 365351), the only significant in vivo metabolite, is also a potent and highly selective PDE4 inhibitor (IC 50 ϭ 20 nM). Both SCH 351591 and SCH 365351 inhibited cytokine production in human blood mononuclear cell preparations. Oral SCH 351591 significantly attenuated allergen-induced eosinophilia and airway hyperreactivity in allergic guinea pigs at doses as low as 1 mg/kg. In this model, oral SCH 365351 showed similar potency. When SCH 351591 was administered orally to allergic cynomolgus monkeys at 3 mg/kg, Ascaris suuminduced lung eosinophilia was blocked. Hyperventilationinduced bronchospasm in nonallergic guinea pigs, a model for exercise-induced asthma, was also suppressed significantly by oral SCH 351591 at 0.3 mg/kg. Cilomilast (SB 207499; Ariflo), a PDE4 inhibitor currently being developed for asthma and chronic obstructive pulmonary disease (COPD), was 10-to 30-fold less potent than SCH 351591 at inhibiting guinea pig lung eosinophilia and hyperventilation-induced bronchospasm. In a ferret model of emesis, maximum nonemetic oral doses of SCH 351591 and cilomilast were 5 and 1 mg/kg, respectively. Comparison of plasma levels at these nonemetic doses in ferrets to those at doses inhibiting hyperventilation-induced bronchospasm in guinea pigs gave a therapeutic ratio of 16 for SCH 351591 and 4 for cilomilast. Thus, SCH 351591 exhibits a promising preclinical profile as a treatment for asthma and COPD.

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Phosphodiesterase (PDE) 4 inhibitors have been shown to inhibit eosinophil PDE4 activity in vitro and accumulation of eosinophils in experimental airways inflammation. However, direct effects on eosinophil trafficking have not been studied in detail and it is not known if activity in vitro translates into efficacy in vivo. In the present study, we compared the activity of five PDE4 inhibitors in vitro and against trafficking of 111In‐eosinophils in cutaneous inflammation in the guinea‐pig. The rank order of potency for inhibition of PDE4 activity in guinea‐pig eosinophil, neutrophil and macrophage, and human neutrophil lysates was RP73401>SB207499>CDP840>rolipram>LAS31025. On TNFα production by human PBMC, all inhibitors with the exception of rolipram showed potency similar to their effect on neutrophil lysates. In a brain cerebellum binding assay, the rank order of potency at displacing [3H]‐rolipram was RP73401>rolipram>SB207499>CDP840>LAS30125. Trafficking of 111In‐eosinophils to skin sites injected with PAF, ZAP or antigen in sensitized sites was inhibited by oral administration of all PDE4 inhibitors. The rank order of potency was RP73401=rolipram>LAS31025>SB207499>CDP840. With the exception was RP73401, which was the most potent compound in all assays, there was no clear relationship between activity of PDE4 inhibitors in vitro and capacity to inhibit eosinophil trafficking in vivo. Thus, we conclude that in vitro activity of PDE4 inhibitors does not predict in vivo efficacy in an experimental model of eosinophil trafficking. British Journal of Pharmacology (1999) 126, 1863–1871; doi: