Michael Y. Berlin

Histamine H3 Receptor as a Drug Discovery Target

Ever since its pharmacologic discovery in 1983, the histamine H3 receptor has provided a tantalizing target for drug research, 25 years later still to be validated by an approved and marketed product. The H3 receptor is one of the four currently known histamine receptor subtypes (H1-H4). Successful modulation of the histamine effects in the human body was initially achieved through the development of drugs acting at H1 receptors, which were designed to mitigate the consequences of histamine release in an allergic reaction. The ClaritinZyrtec-Allegra trio epitomizing the new generation of nonsedating antihistamines went on to gain tremendous therapeutic and commercial success.At the same time a different class of drugs was shown to mediate secretion of gastric acid through selective antagonism of the H2 receptors, a discovery that eventually led to the development of Tagamet and Zantac. The success of these drugs understandably heightened interest in the therapeutic and commercial potential of ligands of theH3 and of the more recently discovered H4 receptor. 4,5 With pharmaceutical industry efforts naturally delayed in the early years by the challenges of H3 biology, including lack of molecular identification of the human H3 receptor, medicinal chemistry programs finally shifted into high gear in the early 2000s. Importantly, the H3 receptor position at the crossroads of neurotransmission suggests an abundance of therapeutic applications for small-molecule receptor modulators. Clearly a challenge to the tractability of in vitro and in vivo data, the complexity of H3 biology has nevertheless set up expectations of a large payout at the end of the journey. While in mid-2009 this journey still remains to be successfully completed, a number of ongoing H3 clinical programs, including several in phase II, an abundance ofH3 publications, and extensive H3 patenting activity testify to the high level of interest in this area. Needless to say, the current medicinal chemistry programs are based on the monumental amount of research effort that has gone into establishing various aspects of H3 receptor biology.

Recent advances in the development of histamine H3 antagonists.

The histamine H3 receptor is involved in the central and peripheral regulation of levels of histamine and other neurotransmitters (e.g., acetylcholine, noradrenaline, dopamine, serotonin and GABA), which sets it up as a target in the treatment of various CNS (e.g., depression, schizophrenia, ADHD, dementia, neuropathic pain and sleep disorders), metabolic syndrome (e.g., obesity) and allergic disorders. Novel chemical series from the most recent 2 years of patent literature have been reviewed. While overall structural diversity is moderate, these represent or relate to some of the compounds progressing through clinical trials (e.g., GSK-189254). However, an H3 receptor drug still has yet to reach the market. Patenting activity is likely to remain high in the near future, bolstered by the commercial promise of potential H3 receptor drugs.

Identification of a novel, orally bioavailable histamine H3 receptor antagonist based on the 4-benzyl-(1H-imidazol-4-yl) template

A novel series of histamine H(3) receptor antagonists, based on the 4-benzyl-(1H-imidazole-4-yl) template, incorporating urea and carbamate linkers has been prepared. Compound 3j is a selective H(3) antagonist and demonstrates excellent oral plasma levels in the rat and monkey.