A Novel Class of Orally Active Non-Peptide Bradykinin B<sub>2</sub> Receptor
Antagonists. 3. Discovering Bioisosteres of the Imidazo[1,2-<i>a</i>]pyridine Moiety
Yoshito Abe
Hiroshi Kayakiri
Shigeki Satoh
Takayuki Inoue
Yuki Sawada
Noriaki Inamura
Masayuki Asano
Ichiro Aramori
Chie Hatori
Hiroe Sawai
Teruo Oku
Hirokazu Tanaka
10.1021/jm980300f.s001
https://acs.figshare.com/articles/journal_contribution/A_Novel_Class_of_Orally_Active_Non-Peptide_Bradykinin_B_sub_2_sub_Receptor_Antagonists_3_Discovering_Bioisosteres_of_the_Imidazo_1_2-_i_a_i_pyridine_Moiety/3683871
Recently we reported on overcoming the species difference of our first orally active non-peptide
bradykinin (BK) B<sub>2</sub> receptor antagonists, incorporating an 8-[[3-(<i>N</i>-acylglycyl-<i>N</i>-methylamino)-2,6-dichlorobenzyl]oxy]-3-halo-2-methylimidazo[1,2-<i>a</i>]pyridine skeleton, leading to identification
of the first clinical candidate <b>4a</b> (FR167344). With this potent new lead compound in hand,
we then investigated further refinement of the basic framework by replacement of the imidazo[1,2-<i>a</i>]pyridine moiety and discovered several bioisosteric heterocycles. Extensive optimization
of these new heteroaromatic derivatives revealed the detailed structure−activity relationships
(SAR) around the imidazo[1,2-<i>a</i>]pyridine ring and the 2,6-dichlorobenzyl moiety, leading to
the discovery of our second clinical candidate <b>87b</b> (FR173657) which inhibited the specific
binding of [<sup>3</sup>H]BK to recombinant human B<sub>2</sub> receptors expressed in Chinese hamster ovary
(CHO) cells and guinea pig ileum membrane preparations expressing B<sub>2</sub> receptors with IC<sub>50</sub>'s
of 1.4 and 0.46 nM, respectively. This compound also displayed excellent in vivo functional
antagonistic activity against BK-induced bronchoconstriction in guinea pigs with an ED<sub>50</sub> value
of 0.075 mg/kg by oral administration. Further modifications of the terminal substituents on
the pyridine moiety led to a novel pharmacophore and resulted in the identification of <b>99</b>
(FR184280), whose IC<sub>50</sub> value for human B<sub>2</sub> receptors (0.51 nM) was comparable to that of the
second-generation peptide B<sub>2</sub> antagonist Icatibant.
1998-09-19 00:00:00
BK
guinea pig ileum membrane preparations
B 2 receptors
compound
identification
imidazo
FR
pyridine moiety
candidate 87 b
B 2 receptor antagonists
SAR
nM
Chinese hamster ovary
ED 50 value
CHO
IC 50 value