No abstract

Following the discovery of the human histamine H4 receptor, a high throughput screen of our corporate compound collection identified compound 6 as a potential lead. Investigation of the SAR resulted in the discovery of novel compounds 10e and 10l, which are the first potent and selective histamine H4 receptor antagonists to be described.

Three series of H(4) receptor ligands, derived from indoly-2-yl-(4-methyl-piperazin-1-yl)-methanones, have been synthesized and their structure-activity relationships evaluated for activity at the H(4) receptor in competitive binding and functional assays. In all cases, substitution of small lipophilic groups in the 4 and 5-positions led to increased activity in a [(3)H]histamine radiolabeled ligand competitive binding assay. In vitro metabolism and initial pharmacokinetic studies were performed on selected compounds leading to the identification of indole 8 and benzimidazole 40 as potent H(4) antagonists with the potential for further development. In addition, both 8 and 40 demonstrated efficacy in in vitro mast cell and eosinophil chemotaxis assays.

Neuropeptide Y (NPY) is a 36-amino acid peptide discovered in the early 1980s that belongs to a family of peptides that includes pancreatic polypeptides (PP) and peptide YY (PYY) (Tatemoto and Mutt, 1980). NPY is widely distributed in the central and peripheral nervous systems (for reviews, see Blomqvist and Herzog, 1997;Gehlert, 1999;Wieland et al., 2000;Kask et al., 2002;Malmstrom, 2002;Thorsell and Heilig, 2002). In the brain, NPY is the most abundant neuropeptide yet identified and its localization suggests an involvement in a variety of physiological processes, including anxiety, food intake, water consumption, circadian rhythms, hormone release, learning, and memory.The use of various cloning techniques has resulted in the identification of five receptors to date (Y 1 , Y 2 , Y 4 , Y 5 , and y 6 ) (Herzog et al., 1992;Larhammar et al., 1992;Bard et al., 1995;Gerald et al., 1995Gerald et al., , 1996Gregor et al., 1996;Hu et al., 1996;Matsumoto et al., 1996;Weinberg et al., 1996), all of them belong to the superfamily of G protein-coupled receptors. All NPY receptor subtypes are expressed in several species, including human, except the y 6 , which is absent in rat and not functional in the human and primates (Blomqvist and Herzog, 1997

Histamine is a biogenic amine that plays a host of physiological roles and the three major functions for histamine have been largely defined by the activity of three receptors. The inflammatory wheal and flare response is driven by the H1 receptor [1]. The H2 receptor controls gastric acid secretion in the gut [2]. The H3 receptor is involved in neurotransmitter release in the central nervous system [3]. The recent discovery of the histamine H4 receptor by several groups has lead to the re-evaluation of the physiological role for histamine.

Highly stereoselective syntheses of aldols 8a-c corresponding to the C(13)-C(25) segment of bafilomycin A(1) were developed by routes involving fragment assembly aldol reactions of chiral aldehyde 6a and the chiral methyl ketones 7. A remote chelation effect plays a critical role in determining the stereoselectivity of the key aldol coupling of 6a and the lithium enolate of 7b. The protecting group for C(23)-OH of the chiral aldehyde fragment also influences the selectivity of the lithium enolate aldol reaction. In contrast, the aldol reaction of 6a and the chlorotitanium enolates of 7a,c were much less sensitive to the nature of the C(15)-hydroxyl protecting group. Studies of the reactions of chiral aldehydes with Takai's (gamma-methoxyallyl)chromium reagent 40 are also described. The stereoselectivity of these reactions is also highly dependent on the protecting groups and stereochemistry of the chiral aldehyde substrates.

In our evolving studies on the chemistry of nonracemic a-and y-oxygenated allylic stannanes as reagents for Se2' additions to aldehydes, we found improved symanti diastereoselectivity for OTBS vs OMOM methallyl derivatives 3 and 4 (eq l).1

No abstract