Design and Evaluation of Novel Biphenyl Sulfonamide Derivatives with Potent Histamine H3 Receptor Inverse Agonist Activity

• Published in: Journal of medicinal chemistry Vol. 52; no. 18; pp. 5603 - 5611
• Main Authors: Covel, Jonathan A., Santora, Vincent J., Smith, Jeffrey M., Hayashi, Rena, Gallardo, Charlemagne, Weinhouse, Michael I., Ibarra, Jason B., Schultz, Jeffrey A., Park, Douglas M., Estrada, Scott A., Hofilena, Brian J., Pulley, Michelle D., Smith, Brian M., Ren, Albert, Suarez, Marissa, Frazer, John, Edwards, Jeffrey, Hauser, Erin K., Lorea, Jodie, Semple, Graeme, Grottick, Andrew J.
• Format: Journal Article
• Language: English
• Published: Columbus, OH American Chemical Society 24-09-2009
• Subjects: Biological and medical sciences; Medical sciences; Miscellaneous; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology. Drug treatments; H3 histamine receptor; Rat; Rodentia; Central nervous system; Oral administration; In vitro; Encephalon; In vivo; Tissue; Vertebrata; Chemotherapy; Mammalia; Treatment; Structure activity relation; Inverse agonist; Animal; Distribution; Affinity; Pharmacokinetics; Chemical synthesis; Polydipsia
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm900857n

Antagonism of the histamine-H3 receptor is one tactic being explored to increase wakefulness for the treatment of disorders such as excessive daytime sleepiness (EDS) as well as other sleep or cognitive disorders. Phenethyl-R-2-methylpyrrolidine containing biphenylsulfonamide compounds were shown to be potent and selective antagonists of the H3 receptor. Several of these compounds demonstrated in vivo activity in a rat model of (R)-α-methyl histamine (RAMH) induced dipsogenia, and one compound (4e) provided an increase in wakefulness in rats as measured by polysomnographic methods. However, more detailed analysis of the PK/PD relationship suggested the presence of a common active metabolite which may preclude this series of compounds from further development.