Hetrazepines as antagonists of platelet activating factor

Actions of PAF receptor antagonists in horses with the allergic skin disease sweet itch

“…The lack of inhibition of Culicoides antigen-induced oedema by WEB 2086 could be explained if local concentrations of the antagonist were not maintained at an effective level for a sufficient period of time. Alternatively, WEB 2086 may not cross cell membranes to reach its site of action [17]. In contrast to the effects of local administration, intravenous infusion of WEB 2086 reduced oedema produced by Culicoides antigen in the early and late phases.…”

A Monte Carlo pharmacophore generation procedure: Application to the human PAF receptor

“…The triazole sp 2 nitrogen at the 8-position of the hetrazepine nucleus of WEB 2086 was chosen as the hydrogen-bond acceptor, since the SAR [26] for the methyl group at the adjacent 9-position is similar to that observed for the heterocyclic methyl group of both UK-74,505 [25] and BB-182 [21]. However, it should be noted that there are data from the SAR for imidazole analogues of WEB 2086 to suggest that it is the triazole sp 2 nitrogen at the 7-position of the hetrazepine nucleus that provides the key interaction [26,44]. Conformational searching was performed using the SEARCH program in SYBYL [27] with distance constraints corresponding to the pharmacophore distances in Table 4.…”

“…A number of other PAF antagonists also possess a heterocyclic sp 2 nitrogen such as the 3-pyridyl derivatives RP 59227 [22], YM461 [23a,b] and Ro 24-0238 [24], imidazo [4,5-c]pyridine compounds such as UK-74,505 [25] and hetrazepine derivatives such as WEB 2086 [26]. It was hypothesized that these compounds might bind to the PAF receptor in the manner described by Tilley et al [20] since in addition to the sp 2 nitrogen these compounds possess some other structural features in common; a carbonyl/ sulphonyl moiety, a 'lipophilic' group, and for some, but not all, compounds a sulphur atom.…”

“…For example, for analogues of the pyridine derivative Ro 24-0238 the 2-pyridyl and 4-pyridyl compounds are less potent than the 3-pyridyl compounds [24]. Similarly, for sp 2 nitrogen heterocyclic PAF antagonists that possess a sulphur atom, its presence and position appears to be important for activity [23,26]. The SAR data for the role of the carbonyl/sulphonyl group is less clear and there are a few examples of sp 2 nitrogen heterocycle PAF antagonists that do not possess a carbonyl/sulphonyl group [8].…”

Failure of the platelet-activating-factor antagonist WEB 2086 BS for treatment of chronic autoimmune thrombocytopenia

“…This lipid mediator has a broad biological action and may be involved in different pathological processes including i m m u n o l o g i c a l diseases such as asthma, i n f l a m m a t i o n or transplant rejection [7,13]. WEB 2086 BS is a potent competitive inhibitor for the binding of PAF to its putative receptor on h u m a n cells [8,17]. It was well tolerated in volunteers and almost completely inhibits PAF-induced platelet aggregation ex vivo [1-41.…”