Recently we found that synthetic compounds containing amino group linked to hydrophobic or aromatic moiety are potent modulators of the proton-gated channels (ASICs). These structures have clear similarity with ligands of histamine receptors. We have also demonstrated that histamine potentiates homomeric ASIC1a by shifting its activation dependence to less acidic conditions. In the present work the action of a series of histamine receptors ligands on recombinant ASIC1a and ASIC2a was characterized. Two types of action were found for ASIC1a. 1-methylhistamine, N-alpha-methylhistamine, dimaprit and thioperamide caused significant potentiation, which was pH-dependent and voltage-independent. The H4R antagonist A943931 caused inhibition, which is likely due to voltage-dependent pore block. ASIC2a were virtually insensitive to the drugs tested. We conclude that ligands of histamine receptors should also be considered as ASIC modulators.

23 Oct 2008·Journal of Medicinal ChemistryQ1 · MEDICINE

Rotationally Constrained 2,4-Diamino-5,6-disubstituted Pyrimidines: A New Class of Histamine H₄Receptor Antagonists with Improved Druglikeness and in Vivo Efficacy in Pain and Inflammation Models

Q1 · MEDICINE

Article

Author: Liu, Huaqing ; Drizin, Irene ; Hsieh, Gin C. ; Esbenshade, Timothy A. ; Miller, Thomas R. ; Brioni, Jorge D. ; Cowart, Marlon D. ; Witte, David G. ; Marsh, Kennan C. ; Altenbach, Robert J. ; Adair, Ronald M. ; Wishart, Neil ; Milicic, Ivan ; Wetter, Jill M. ; Fix-Stenzel, Shannon R. ; Sullivan, James P. ; Bettencourt, Brian M. ; McPherson, Michael J. ; Honore, Prisca

A new structural class of histamine H 4 receptor antagonists (6-14) was designed based on rotationally restricted 2,4-diaminopyrimidines. Series compounds showed potent and selective in vitro H 4 antagonism across multiple species, good CNS penetration, improved PK properties compared to reference H 4 antagonists, functional H 4 antagonism in cellular and in vivo pharmacological assays, and in vivo anti-inflammatory and antinociceptive efficacy. One compound, 10 (A-943931), combined the best features of the series in a single molecule and is an excellent tool compound to probe H 4 pharmacology. It is a potent H 4 antagonist in functional assays across species (FLIPR Ca (2+) flux, K b < 5.7 nM), has high (>190x) selectivity for H 4, and combines good PK in rats and mice (t 1/2 of 2.6 and 1.6 h, oral bioavailability of 37% and 90%) with anti-inflammatory activity (ED 50 = 37 micromol/kg, mouse) and efficacy in pain models (thermal hyperalgesia, ED 50 = 72 micromol/kg, rat).

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Indication	Highest Phase	Country/Location	Organization	Date
Inflammation	Preclinical	United States	Abbott Laboratories	26 Sep 2008
Pain	Preclinical	United States	Abbott Laboratories	26 Sep 2008

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