H3 antagonists

The definitive identifieation of a therapeutie raison d etre for H3 antagonists will happen in the elinie. A handful of H3 ligands are reported to have entered elinieal testing. ABT-834 entered Phase-I trials for the indieation of cognitive disorders in May 2003 but no news has been reported since that time. GT-2331 (11) was approved for Phase-II clinical trials in 1999 but no news has been reported since then [4]. At this point, there are no data available to assess the therapeutic potential in human disease (See Table 5.1). 

Numerous pharmaceutical companies and academic laboratories have published data on a wide variety of small molecule H3 antagonists/inverse agonists. Highlights of the data reported since the last review in this book series [67] will be reported here. 

The collaboration between several academic laboratories has shown that the imidazole moiety on some of the earlier H3 antagonists can be replaced with a piperidine. For example, the ciproxifan analogue (16) has a pK of 8.4 in rat cerebral cortex [80]. This compound showed in vivo efficacy after p.o. administration to a mouse. Other piperidines studied by these researchers include (17) (H3 p 2 = 7.21 in guinea-pig ileum) [81] and (18) (human K[ — 2.8 nM, p 2 = 7.42 in guinea-pig ileum) [82]. The authors have also found that benzyl ethers such as (19) are somewhat weaker H3 antagonists (p 2 = 6.3 in guinea-pig ileum) [83]. 

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 pM). Medicinal chemistry efforts then led to the discovery of the piperidine propyloxy compound (31) [100]. This imidazopyridine has a A) at the human H3 receptor of 2nM and... 

In efforts designed to replace the imidazopyridine ring system, indolizi-dines such as (32) [101] (human H3 if = 13 nM), and related heterocycles [102-104] were identified as potent H3 antagonists. Indolizidine (32) suffered from rapid metabolism in human liver microsomes, however, substitution on the indolizidine ring suppresses this liability. 

Researchers at GlaxoSmithKline have numerous recent patent applications describing several series of H3 antagonists including the benzazapines (41) [115] and (42) [116], quinolizidines (43) [117], isoindolines (44) [118], and the piperidine amides (45) [119] and (46) [120]. All of these structures were disclosed as functional H3 antagonists. 

In addition to the imidazole-based compounds detailed earlier, more recently the Schering-Plough group reported on several new series of H3 antagonists including oximes (47) [121], benzimidazoles (48) [122], benzimidazolones (49) [123], and indoles (50) [124]. All of the compounds shown have K] of less than 10 nM in guinea-pig brain. 

Researchers at Novo Nordisk have found that certain acyl piperazines are potent H3 antagonists [125, 126]. Examples include structures (51) and (52), both of which have a if of 1.2 nM against human H3. The group... 

Researchers at Lilly have prepared a series of alkylamine H3 antagonists. Examples include the amide (57), which has a of 1.05 nM and the tetra-hydroisoquinoline (58), which has a A) of 0.37 nM [132]. Both compounds are inactive at the Hi, H2, and H4 receptors. This same group also disclosed a series of azepines, represented by (59) (H3 A j = 0.85 nM) and (60) [133]. Compound (60) is reported to have 100% bioavailability and a 12.4 h half-life in rat. Related dihydroindoles such as (61) (A j = 0.5nM) and tetra-hydroquinolines were also shown to be H3 antagonists [134]. 

Barbier, A. J., Berridge, C Dugovic, C. et al. (2004). Acute wake-promoting actions of JNJ-5207852, a novel, diamine-based H3 antagonist. Br. ]. Pharmacol. 143, 649-61. 

Monti, J. M., Jantos, H., Ponzoni, A Monti, D. (1996). Sleep and waking during acute histamine H3 agonist BP 2.94 or H3 antagonist carboperamide (MR 16155) administration in rats. Neuropsychopharmacology 15, 31-5. 

The stimulatory effects of H3 antagonists on brain histamine dynamics were initially attributed to the... 

Drugs that act on the H3 receptor are being developed for the treatment of obesity, sleep disturbances, epilepsy and cognitive disorders. The ability of histamine to promote arousal, suppress appetite, elevate seizure threshold and stimulate cognitive processes implies that compounds able to enhance the release of neuronal histamine should mimic these effects. Several H3 antagonists currently in development demonstrate such activity and show promise as effective and novel therapeutic agents [40, 84-86]. Because H3 agonists suppress the release of... 

Wieland, K., Bongers, G., Yamamoto, Y. etal. Constitutive activity of histamine H3 receptors stably expressed in SK-N-MC cells display of agonism and inverse agonism by H3 antagonists. /. Pharmacol. Exp. Ther. 299 908-914, 2001. 

Recent Advances in Drug Discovery of Histamine H3 Antagonists... 

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