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In vitro Optimization of Structure Activity Relationships of Analogues of A‐331440 Combining Radioligand Receptor Binding Assays and Micronucleus Assays of Potential Antiobesity Histamine H 3 Receptor Antagonists
Author(s) -
Hancock Arthur A.,
Diehl Marilyn S.,
Faghih Ramin,
Bush Eugene N.,
Krueger Kathleen M.,
Krishna Gopala,
Miller Thomas R.,
Nguyen Phong,
Pratt John K.,
Cowart Marlon D.,
Esbenshade Timothy A.,
Jacobson Peer B.
Publication year - 2004
Publication title -
basic and clinical pharmacology and toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.805
H-Index - 90
eISSN - 1742-7843
pISSN - 1742-7835
DOI - 10.1111/j.1742-7843.2004.950307.x
Subject(s) - genotoxicity , chemistry , stereochemistry , radioligand , potency , histamine , in vitro , receptor , radioligand assay , micronucleus test , pharmacology , biochemistry , biology , toxicity , organic chemistry
A‐331440 {4′‐[3‐(3( R )‐(dimethylamino)‐pyrrolidin‐1‐yl)‐propoxy]‐biphenyl‐4‐carbonitrile}, a potent and selective antagonist of histamine H 3 receptors, yielded positive results in an in vitro micronucleus assay, predictive of genotoxicity in vivo . Because this compound has highly favourable properties and potential as an antiobesity agent, new compounds of this general chemical class were sought that would retain or improve upon the high potency and selectivity of A‐331440 for H 3 receptors, but would lack the potential for genotoxicity obtained with that compound. Our working hypothesis was that the biphenyl rings in A‐331440 might contribute to interactions with DNA and thereby predispose toward genotoxicity. Toward this end, several analogues were prepared, with substituents introduced onto the biaryl ring to alter the orientation, electronegativity, and polarity of this moiety, and were tested for their radioligand binding potency and selectivity and their propensity to induce genotoxicity in the in vitro micronucleus assay. Using this strategy, novel compounds were discovered that retained or improved upon the potency and selectivity of A‐331440 for H 3 receptors and were devoid of genotoxicity in vitro. Of these, the simple mono‐ and di‐fluorinated analogues (A‐417022 [4′‐{3‐[(3 R )‐3‐(dimethylamino)‐1‐pyrrolidinyl]propoxy}‐3′‐fluoro‐1,1′‐biphenyl‐4‐carbonitrile] and A‐423579 [4′‐{3‐[(3 R )‐3‐(dimethylamino)‐1‐pyrrolidinyl]‐propoxy}‐3′,5′‐difluoro‐1,1′‐biphenyl‐4‐carbonitrile], respectively) were found to bind to H 3 receptors at least as potently as A‐331440, while lacking genotoxicity in the micronucleus assay. The reason of the lack of genotoxicity of the fluorinated analogues is unclear, but is especially noteworthy in light of the general principle that fluorine and hydrogen are very similar in size. Therefore, these fluorinated analogues of A‐331440 represented the most potent and potentially safest compounds for further evaluation as antiobesity leads. Preliminary findings with one of these examples, A‐417022, in a mouse model of obesity are presented.