Cn

L-tartrate

Further modifications of (26) led to the oxadiazoles as depicted by (28) [94]. Some of the oxadiazoles have improved human H3 affinity and (28) is efficacious in the dipsogenia model after i.p. administration. However, the molecular weight and log P of these H3 ligands is rather high.

Most recently, the Abbott group disclosed a series of benzofurans with potent affinity for the human and rat receptors. ABT-239 (29) is one of the more extensively profiled members of this series. (29) has a K of 0.45 nM at the human receptor [95], good rat pharmacokinetics and demonstrated efficacy in models of cognition [96]. Recently, a scaleable synthesis of ABT-239 has been reported [97] and the researchers have published detailed accounts on the pre-clinical pharmacokinetics and efficacy of this compound [98, 99], indicating continued interest in this series of H3 antagonists.

The group at Johnson and Johnson has published several reports on their efforts to find potent H3 antagonists. High-throughput screening using the recombinant human receptor identified the imidazopyridine RWJ-20085 (30) as a weak H3 receptor ligand (K = 4 mM). Medicinal chemistry efforts then led to the discovery of the piperidine propyloxy compound (31) [100]. This imidazopyridine has a K at the human H3 receptor of 2nM and

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