Julie B.H. Warneck

Synthesis and profile of SCH351591, a novel PDE4 inhibitor

The syntheses and pharmacological profiles of some 2-trifluoromethyl-8-methoxyquinoline-5-carboxamides are described. SCH351591 is a potent selective inhibitor of phosphodiesterase type 4 (PDE4).

8-Methoxyquinolines as PDE4 inhibitors

The synthesis and pharmacological profile of a novel series of 2-substituted 8-methoxyquinolines is described. The 2-trifluoromethyl compound was found to be a potent inhibitor of phosphodiesterase type 4 (PDE4).

A comparison of the inhibitory activity of PDE4 inhibitors on leukocyte PDE4 activity in vitro and eosinophil trafficking in vivo.

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.

Aryl sulfonamides as selective PDE4 inhibitors

A series of novel selective phosphodiesterase 4 (PDE4) inhibitors has been developed which displays activity both in vitro and in vivo. These compounds possess good selectivity for the catalytic site of PDE4 over the high affinity Rolipram binding site. In vivo studies demonstrate a reduced propensity to display the emetic side effects which are commonly observed with PDE4 inhibitors.

PDE4 inhibitors: New xanthine analogues

Novel xanthine analogues are described which are selective PDE4 inhibitors with improved therapeutic potential over theophylline.

7-Methoxyfuro[2,3-c]pyridine-4-carboxamides as PDE4 inhibitors: a potential treatment for asthma.

The synthesis and pharmacological profile of a novel series of 7-methoxy-furo[2,3-c]pyridine-4-carboxamides is described. Some of these compounds were found to be potent inhibitors of phosphodiesterase type 4 (PDE4).

7-Methoxybenzofuran-4-carboxamides as PDE 4 inhibitors: a potential treatment for asthma.

The synthesis and pharmacological profile of a novel series of 7-methoxybenzofuran-4-carboxamides is described. Some of these compounds were found to be potent inhibitors of phosphodiesterase type 4 (PDE4).

Silicon analogues of the nonpeptidic GnRH antagonist AG-045572: syntheses, crystal structure analyses, and pharmacological characterization.

AG‐045572 (CMPD1, 1 a) is a nonpeptidic gonadotropin‐releasing hormone (GnRH) antagonist that has been investigated for the treatment of sex hormone‐related diseases. In the context of systematic studies on sila‐substituted drugs, the silicon analogue disila‐AG‐045572 (1 b) and its derivative 2 were prepared in multi‐step syntheses and characterized by elemental analyses (C, H, N), NMR spectroscopic studies (1H, 13C, 29Si), and single‐crystal X‐ray diffraction. The pharmacological properties of compounds 1 a, 1 b, and 2 were compared in terms of their in vitro potency at cloned human and rat GnRH receptors. Compounds 1 a and 2 were also examined in regard to their pharmacokinetics and in vivo efficacy in both castrated rat (luteinizing hormone (LH) suppression) and intact rat (testosterone suppression) models. The efficacy and pharmacokinetic profiles of 1 a and its silicon‐containing analogue 2 appear similar, indicating that replacement of the 5,6,7,8‐tetrahydronaphthalene ring system by the 1,3‐disilaindane skeleton led to retention of efficacy. Therefore, the silicon compound 2 represents a novel drug prototype for the design of potent, orally available GnRH antagonists suitable for once‐daily dosing.

Synthesis and evaluation of a novel series of phosphodiesterase IV inhibitors. A potential treatment for asthma

The synthesis and pharmacological profile of a novel series of potent and selective phosphodiesterase type IV (PDE IV) inhibitors is described.

8-Methoxyquinoline-5-carboxamides as PDE4 inhibitors: A potential treatment for asthma

A series of bicyclic heteroaryl ring systems was considered as a replacement for the 3-cyclopentyloxy-4-methoxyphenyl moiety in rolipram resulting in the discovery of 8-methoxyquinoline-5-carboxamides as potent inhibitors of phosphodiesterase type 4 (PDE4).