In vitro Optimization of Structure Activity Relationships of Analogues of A‐331440 Combining Radioligand Receptor Binding Assays and Micronucleus Assays of Potential Antiobesity Histamine H3 Receptor Antagonists

• DOI: 10.1111/j.1742-7843.2004.950307.x
• Publication Date: 2004-09-24T16:01:59Z
• Authors: Arthur A. Hancock; Marilyn S. Diehl; Ramin Faghih; Eugene N. Bush; Kathleen M. Krueger; Gopala Krishna; Thomas R. Miller; Denise M.; Wilcox; Phong Nguyen; John K. Pratt; Marlon D. Cowart; Timothy A. Esbens...; Peer B. Jacobson
• Keywords: Radioligand; Radioligand Assay

Abstract: 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 vitro micronucleus assay, predictive genotoxicity vivo . Because this compound has highly favourable properties potential as antiobesity agent, new compounds general chemical class were sought that would retain or improve upon the high potency selectivity for but lack obtained with compound. Our working hypothesis was biphenyl rings might contribute to interactions DNA thereby predispose toward genotoxicity. Toward end, several analogues prepared, substituents introduced onto biaryl ring alter orientation, electronegativity, polarity moiety, tested their radioligand binding propensity induce assay. Using strategy, novel discovered retained improved receptors devoid vitro. Of these, simple mono‐ di‐fluorinated (A‐417022 [4′‐{3‐[(3 )‐3‐(dimethylamino)‐1‐pyrrolidinyl]propoxy}‐3′‐fluoro‐1,1′‐biphenyl‐4‐carbonitrile] A‐423579 )‐3‐(dimethylamino)‐1‐pyrrolidinyl]‐propoxy}‐3′,5′‐difluoro‐1,1′‐biphenyl‐4‐carbonitrile], respectively) found bind at least potently A‐331440, while lacking The reason fluorinated is unclear, especially noteworthy light principle fluorine hydrogen are very similar size. Therefore, these represented most potentially safest further evaluation leads. Preliminary findings one examples, A‐417022, mouse model obesity presented.