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

Abstract

Antagonism of the histamine-H(3) 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 H(3) receptor. Several of these compounds demonstrated in vivo activity in a rat model of (R)-alpha-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.

Lead Optimization of a Pyrazole Sulfonamide Series ofTrypanosoma bruceiN-Myristoyltransferase Inhibitors: Identification and Evaluation of CNS Penetrant Compounds as Potential Treatments for Stage 2 Human African Trypanosomiasis

“…It is notable that there are very few examples of CNS penetrant secondary sulfonamides in the literature. − The secondary sulfonamide has an appreciable acidity, particularly in compounds where the sulfonyl aromatic bears two halogen atoms (i.e., p K a of 7 = 6.9 ± 0.5, p K a of 1 = 7.0 ± 0.5, calculated using ACDlabs software, version 11.02), suggesting the sulfonamide is significantly ionized at physiological pH. Moreover, the secondary sulfonamide exerts a considerable contribution to the overall PSA of compounds in this series (approximately 54 Å 2 ).…”

“…Prototypical Procedure for N-Alkylation of a Sulfonamide with an Alkyl Halide: 4-Bromo-N-methyl-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzenesulfonamide (24). Sodium hydride (95% w/w, 88 mg, 3.48 mmol) was added portionwise to a solution of 4-bromo-N-(1,3,5trimethyl-1H-pyrazol-4-yl)-benzenesulfonamide (1.0 g, 2.91 mmol) in DMF (10.0 mL) at 0 °C.…”

Novel sulfonylurea derivatives as H3 receptor antagonists. Preliminary SAR studies

“…[34] This problem has recently been addressed. [35] In an attempt to overcome hERG-channel inhibition related to H 3 antagonists, we decided to evaluate all of the synthesized compounds for the hERG ion channel inhibitory affinity.…”

A Method for the Racemization of 2-Methylpyrrolidine: A Histamine H3 Receptor Pharmacophore

“…For these reasons the researchers are now emphasizing the development of nonimidazole-based histamine H 3 receptor antagonists. Figure summarizes these H 3 receptor antagonists which have ( R )- 1 as a common pharmacophore …”