128563-34-8Relevant academic research and scientific papers
Multivalent design of long-acting β2-adrenoceptor agonists incorporating biarylamines
Jacobsen, John R.,Aggen, James B.,Church, Timothy J.,Klein, Uwe,Pfeiffer, Juergen W.,Pulido-Rios, Teresa M.,Thomas, G. Roger,Yu, Cecile,Moran, Edmund J.
, p. 2625 - 2630 (2014/06/09)
A series of potent β2-adrenoceptor agonists incorporating a biarylamine secondary binding group was identified. The previously reported milveterol (5), identified by a multivalent approach and containing a typical β2-agonist primary binding group linked via a phenethylamine linker to a hydrophilic secondary binding group, served as an initiation point. A more hydrophobic set of secondary binding groups was explored, prepared rapidly from a common intermediate by Buchwald-Hartwig amination. TD-5471 (25), a potent and selective full agonist of the human β2- adrenoceptor, was identified as the most promising agent. It is potent, with slow onset in an in vitro guinea pig trachea model and shows a dose-dependent and long duration of action in an in vivo guinea pig model of bronchoprotection. TD-5471 is structurally differentiated from milveterol and its long duration of action is consistent with a correlation with hydrophobicity observed in other long-acting β2-agonist discovery programs.
Discovery of a novel series of biphenyl benzoic acid derivatives as potent and selective human β3-adrenergic receptor agonists with good oral bioavailability. Part I
Imanishi, Masashi,Tomishima, Yasuyo,Itou, Shinji,Hamashima, Hitoshi,Nakajima, Yutaka,Washizuka, Kenichi,Sakurai, Minoru,Matsui, Shigeo,Imamura, Emiko,Ueshima, Koji,Yamamoto, Takao,Yamamoto, Nobuhiro,Ishikawa, Hirofumi,Nakano, Keiko,Unami, Naoko,Hamada, Kaori,Matsumura, Yasuhiro,Takamura, Fujiko,Hattori, Kouji
, p. 1925 - 1944 (2008/12/20)
A novel class of biphenyl analogues containing a benzoic acid moiety based on lead compound 8i have been identified as potent and selective human β3 adrenergic receptor (β3-AR) agonists with good oral bioavailability and long plasma half-life. After further substituent effects were investigated at the terminal phenyl ring of lead compound 8i, we have discovered that more lipophilic substitution at the R position improved potency and selectivity. As a result of these studies, 10a and 10e were identified as the leading candidates with the best balance of potency, selectivity, and pharmacokinetic profiles. In addition, compounds 10a and 10e were evaluated to be efficacious for a carbachol-induced increase of intravesical pressure, such as an overactive bladder model in anesthetized dogs. This represents the first demonstrated result dealing with β3- AR agonists.
