Discovery of Quinazolines as Histamine H4 Receptor Inverse Agonists Using a Scaffold Hopping Approach

From a series of small fragments that was designed to probe the histamine H4 receptor (H4R), we previously described quinoxaline-containing fragments that were grown into high affinity H4R ligands in a process that was guided by pharmacophore modeling. With a scaffold hopping exercise and using the...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2008-12, Vol.51 (24), p.7855-7865
Main Authors: Smits, Rogier A, de Esch, Iwan J. P, Zuiderveld, Obbe P, Broeker, Joachim, Sansuk, Kamonchanok, Guaita, Elena, Coruzzi, Gabriella, Adami, Maristella, Haaksma, Eric, Leurs, Rob
Format: Article
Language:English
Subjects:
Animals
Anti-Inflammatory Agents - chemistry
Biological and medical sciences
Bones, joints and connective tissue. Antiinflammatory agents
Chemistry, Pharmaceutical - methods
Drug Design
Histamine Agonists - chemistry
Histamine and antagonists. Allergy
Humans
Hydrogen-Ion Concentration
Inhibitory Concentration 50
Kinetics
Medical sciences
Models, Chemical
Models, Molecular
Molecular Conformation
Pharmacology. Drug treatments
Quinazolines - chemistry
Rats
Receptors, G-Protein-Coupled - agonists
Receptors, Histamine
Receptors, Histamine H4
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Summary:From a series of small fragments that was designed to probe the histamine H4 receptor (H4R), we previously described quinoxaline-containing fragments that were grown into high affinity H4R ligands in a process that was guided by pharmacophore modeling. With a scaffold hopping exercise and using the same in silico models, we now report the identification and optimization of a series of quinazoline-containing H4R compounds. This approach led to the discovery of 6-chloro-N-(furan-3-ylmethyl)2-(4-methylpiperazin-1-yl)quinazolin-4-amine (VUF10499, 54) and 6-chloro-2-(4-methylpiperazin-1-yl)-N-(thiophen-2-ylmethyl)quinazolin-4-amine (VUF10497, 55) as potent human H4R inverse agonists (pK i = 8.12 and 7.57, respectively). Interestingly, both compounds also possess considerable affinity for the human histamine H1 receptor (H1R) and therefore represent a novel class of dual action H1R/H4R ligands, a profile that potentially leads to added therapeutic benefit. Compounds from this novel series of quinazolines are antagonists at the rat H4R and were found to possess anti-inflammatory properties in vivo in the rat.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm800876b