The Experts below are selected from a list of 239472 Experts worldwide ranked by ideXlab platform
Yuki Sawada - One of the best experts on this subject based on the ideXlab platform.
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a new series of highly potent non peptide bradykinin b2 receptor antagonists incorporating the 4 heteroarylquinoline framework improvement of aqueous solubility and new insights into Species Difference
Journal of Medicinal Chemistry, 2004Co-Authors: Yuki Sawada, Hiroshi Kayakiri, Yoshito Abe, Keisuke Imai, Tsuyoshi Mizutani, Noriaki Inamura, Masayuki Asano, Ichiro Aramori, Chie Hatori, Akira KatayamaAbstract:Introduction of nitrogen-containing heteroaromatic groups at the 4-position of the quinoline moiety of our non-peptide B2 receptor antagonists resulted in enhancing binding affinities for the human B2 receptor and reducing binding affinities for the guinea pig one, providing new structural insights into Species Difference. A CoMFA study focused on the diversity of the quinoline moiety afforded correlative and predictive QSAR models of binding for the human B2 receptor but not for the guinea pig one. A series of 4-(1-imidazolyl)quinoline derivatives could be dissolved in a 5% aqueous solution of citric acid up to a concentration of 10 mg/mL. A representative compound 48a inhibited the specific binding of [3H]BK to the cloned human B2 receptor expressed in Chinese hamster ovary cells with an IC50 value of 0.26 nM and significantly inhibited BK-induced bronchoconstriction in guinea pigs even at 1 μg/kg by intravenous administration.
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a new series of highly potent non peptide bradykinin b2 receptor antagonists incorporating the 4 heteroarylquinoline framework improvement of aqueous solubility and new insights into Species Difference
Journal of Medicinal Chemistry, 2004Co-Authors: Yuki Sawada, Hiroshi Kayakiri, Yoshito Abe, Keisuke Imai, Tsuyoshi Mizutani, Noriaki Inamura, Masayuki Asano, Ichiro Aramori, Chie Hatori, Akira KatayamaAbstract:Introduction of nitrogen-containing heteroaromatic groups at the 4-position of the quinoline moiety of our non-peptide B2 receptor antagonists resulted in enhancing binding affinities for the human...
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a novel class of orally active non peptide bradykinin b2 receptor antagonists 2 overcoming the Species Difference between guinea pig and man
Journal of Medicinal Chemistry, 1998Co-Authors: Yoshito Abe, Yuki Sawada, Hiroshi Kayakiri, Noriaki Inamura, Masayuki Asano, Chie Hatori, Shigeki Satoh, Takayuki Inoue, Hiroe Sawai, Teruo OkuAbstract:Recently we reported the identification of a series of 8-[[3-(N-acylglycyl-N-methylamino)-2, 6-dichlorobenzyl]oxy]-3-halo-2-methylimidazo[1,2-a]pyridines as the first orally active non-peptide bradykinin (BK) B2 receptor antagonists (1-3). These compounds inhibited the specific binding of [3H]BK to guinea pig ileum membrane preparations expressing B2 receptors with nanomolar IC50's and also displayed in vivo functional antagonistic activities against BK-induced bronchoconstriction in guinea pigs at 1 mg/kg by oral administration. However, it was found that their affinities for the B2 receptors in human A-431 cells (human epidermoid carcinoma) were much lower. Intensive modifications of the terminal substituents at the glycine moiety elucidated the structure-activity relationships (SAR) for human B2 receptors, leading to an extended basic framework which incorporated a novel key pharmacophore. Thus, we overcame the Species Difference and identified the first clinical candidate 18c (FR167344) with IC50's of 0.66 and 1.4 nM for guinea pig ileum and human A-431 cells, respectively. This compound displayed in vivo functional antagonistic activity against BK-induced bronchoconstriction in guinea pigs with an ED50 value of 0.17 mg/kg by oral administration. This novel non-peptide B2 antagonist is extremely potent both in vitro and in vivo by oral administration and is expected to be the first member of a new class of drug for the treatment of various inflammatory diseases.
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a novel class of orally active non peptide bradykinin b2 receptor antagonists 3 discovering bioisosteres of the imidazo 1 2 a pyridine moiety
Journal of Medicinal Chemistry, 1998Co-Authors: Yoshito Abe, Yuki Sawada, Hiroshi Kayakiri, Noriaki Inamura, Masayuki Asano, Ichiro Aramori, Chie Hatori, Shigeki Satoh, Takayuki Inoue, Hiroe SawaiAbstract:Recently we reported on overcoming the Species Difference of our first orally active non-peptide bradykinin (BK) B2 receptor antagonists, incorporating an 8-[[3-(N-acylglycyl-N-methylamino)-2,6-dichlorobenzyl]oxy]-3-halo-2-methylimidazo[1,2-a]pyridine skeleton, leading to identification of the first clinical candidate 4a (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-a]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-a]pyridine ring and the 2,6-dichlorobenzyl moiety, leading to the discovery of our second clinical candidate 87b (FR173657) which inhibited the specific binding of [3H]BK to recombinant human B2 receptors expressed in Chinese hamster ovary (CHO) cells and guinea pig ileum membrane preparations expressing B2 receptors with IC50'...
Yoshito Abe - One of the best experts on this subject based on the ideXlab platform.
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a new series of highly potent non peptide bradykinin b2 receptor antagonists incorporating the 4 heteroarylquinoline framework improvement of aqueous solubility and new insights into Species Difference
Journal of Medicinal Chemistry, 2004Co-Authors: Yuki Sawada, Hiroshi Kayakiri, Yoshito Abe, Keisuke Imai, Tsuyoshi Mizutani, Noriaki Inamura, Masayuki Asano, Ichiro Aramori, Chie Hatori, Akira KatayamaAbstract:Introduction of nitrogen-containing heteroaromatic groups at the 4-position of the quinoline moiety of our non-peptide B2 receptor antagonists resulted in enhancing binding affinities for the human B2 receptor and reducing binding affinities for the guinea pig one, providing new structural insights into Species Difference. A CoMFA study focused on the diversity of the quinoline moiety afforded correlative and predictive QSAR models of binding for the human B2 receptor but not for the guinea pig one. A series of 4-(1-imidazolyl)quinoline derivatives could be dissolved in a 5% aqueous solution of citric acid up to a concentration of 10 mg/mL. A representative compound 48a inhibited the specific binding of [3H]BK to the cloned human B2 receptor expressed in Chinese hamster ovary cells with an IC50 value of 0.26 nM and significantly inhibited BK-induced bronchoconstriction in guinea pigs even at 1 μg/kg by intravenous administration.
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a new series of highly potent non peptide bradykinin b2 receptor antagonists incorporating the 4 heteroarylquinoline framework improvement of aqueous solubility and new insights into Species Difference
Journal of Medicinal Chemistry, 2004Co-Authors: Yuki Sawada, Hiroshi Kayakiri, Yoshito Abe, Keisuke Imai, Tsuyoshi Mizutani, Noriaki Inamura, Masayuki Asano, Ichiro Aramori, Chie Hatori, Akira KatayamaAbstract:Introduction of nitrogen-containing heteroaromatic groups at the 4-position of the quinoline moiety of our non-peptide B2 receptor antagonists resulted in enhancing binding affinities for the human...
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a novel class of orally active non peptide bradykinin b2 receptor antagonists 2 overcoming the Species Difference between guinea pig and man
Journal of Medicinal Chemistry, 1998Co-Authors: Yoshito Abe, Yuki Sawada, Hiroshi Kayakiri, Noriaki Inamura, Masayuki Asano, Chie Hatori, Shigeki Satoh, Takayuki Inoue, Hiroe Sawai, Teruo OkuAbstract:Recently we reported the identification of a series of 8-[[3-(N-acylglycyl-N-methylamino)-2, 6-dichlorobenzyl]oxy]-3-halo-2-methylimidazo[1,2-a]pyridines as the first orally active non-peptide bradykinin (BK) B2 receptor antagonists (1-3). These compounds inhibited the specific binding of [3H]BK to guinea pig ileum membrane preparations expressing B2 receptors with nanomolar IC50's and also displayed in vivo functional antagonistic activities against BK-induced bronchoconstriction in guinea pigs at 1 mg/kg by oral administration. However, it was found that their affinities for the B2 receptors in human A-431 cells (human epidermoid carcinoma) were much lower. Intensive modifications of the terminal substituents at the glycine moiety elucidated the structure-activity relationships (SAR) for human B2 receptors, leading to an extended basic framework which incorporated a novel key pharmacophore. Thus, we overcame the Species Difference and identified the first clinical candidate 18c (FR167344) with IC50's of 0.66 and 1.4 nM for guinea pig ileum and human A-431 cells, respectively. This compound displayed in vivo functional antagonistic activity against BK-induced bronchoconstriction in guinea pigs with an ED50 value of 0.17 mg/kg by oral administration. This novel non-peptide B2 antagonist is extremely potent both in vitro and in vivo by oral administration and is expected to be the first member of a new class of drug for the treatment of various inflammatory diseases.
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a novel class of orally active non peptide bradykinin b2 receptor antagonists 3 discovering bioisosteres of the imidazo 1 2 a pyridine moiety
Journal of Medicinal Chemistry, 1998Co-Authors: Yoshito Abe, Yuki Sawada, Hiroshi Kayakiri, Noriaki Inamura, Masayuki Asano, Ichiro Aramori, Chie Hatori, Shigeki Satoh, Takayuki Inoue, Hiroe SawaiAbstract:Recently we reported on overcoming the Species Difference of our first orally active non-peptide bradykinin (BK) B2 receptor antagonists, incorporating an 8-[[3-(N-acylglycyl-N-methylamino)-2,6-dichlorobenzyl]oxy]-3-halo-2-methylimidazo[1,2-a]pyridine skeleton, leading to identification of the first clinical candidate 4a (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-a]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-a]pyridine ring and the 2,6-dichlorobenzyl moiety, leading to the discovery of our second clinical candidate 87b (FR173657) which inhibited the specific binding of [3H]BK to recombinant human B2 receptors expressed in Chinese hamster ovary (CHO) cells and guinea pig ileum membrane preparations expressing B2 receptors with IC50'...
Tengkuang Yeh - One of the best experts on this subject based on the ideXlab platform.
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biotransformation of 6 methoxy 3 3 4 5 trimethoxy benzoyl 1h indole bpr0l075 a novel antimicrotubule agent by mouse rat dog and human liver microsomes
Drug Metabolism and Disposition, 2007Co-Authors: Hsientsung Yao, Yiwei Chang, Hsingpang Hsieh, Weicheng Chen, Shihjung Lan, Chiungtong Chen, Yusheng Chao, Ling Chang, Hsuyi Sun, Tengkuang YehAbstract:6-Methoxy-3-(3′,4′,5′-trimethoxy-benzoyl)-1H-indole (BPR0L075) is a novel synthetic indole compound with microtubule binding activity. Incubation of BPR0L075 with mouse, rat, dog, and human liver microsomes in the presence of NADPH resulted in the formation of six metabolites. Liquid chromatography-tandem mass spectrometry and comparison with the synthetic reference standards identified two metabolites (M1 and M5) as the products derived from hydroxylation on the indole moiety of the molecule. M3 was also identified as a product derived from hydroxylation, but the structure of this metabolite was not identified because of the lack of a reference standard. M2, M4, and M6 were identified as the products derived from O-demethylation. M2, 6-desmethyl-BPR0L075, was the major metabolite formed by the liver microsomes of the four Species. No qualitative Species Difference in the metabolism of BPR0L075 was observed. There was quantitative Species Difference in the metabolism of BPR0L075 among the four Species. Whereas mouse and rat liver microsomes metabolized BPR0L075 predominantly via O-demethylation, dog liver microsomes metabolized BPR0L075 by O-demethylation and hydroxylation to about the same extent. The rank order of intrinsic clearance rates for the conversion of BPR0L075 to 6-desmethyl-BPR0L075 was mouse > rat > human > dog. Incubation of BPR0L075 with baculovirus-insect cell-expressed human cytochrome P450 (P450) isozymes showed that CYP1A2, 2C9, 2C19, 2D6, 2E1, and 3A4 all catalyzed the O-demethylation and hydroxylation of BPR0L075 but to a different degree. Among the six P450 isozymes tested, CYP1A2 and 2D6 were most active on catalyzing the metabolism of BPR0L075. CYP1A2 catalyzed mainly the formation of M1, M2, and M3. M2 was the predominant metabolite formed by CYP2D6.
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biotransformation of 6 methoxy 3 3 4 5 trimethoxy benzoyl 1 hindole bpr0l075 a novel antimicrotubule agent by mouse rat dog and human liver microsomes
Drug Metabolism and Disposition. 2007 Jul, 2007Co-Authors: Hsientsung Yao, Yiwei Chang, Hsingpang Hsieh, Weicheng Chen, Shihjung Lan, Chiungtong Chen, Yusheng Chao, Ling Chang, Hsuyi Sun, Tengkuang YehAbstract:Methoxy-3-(3,4,5-trimethoxy-benzoyl)-1H-indole (BPR0L075) is a novel synthetic indole compound with microtubule binding activity. Incubation of BPR0L075 with mouse, rat, dog, and human liver microsomes in the presence of NADPH resulted in the forma- tion of six metabolites. Liquid chromatography-tandem mass spectrometry and comparison with the synthetic reference stan- dards identified two metabolites (M1 and M5) as the products derived from hydroxylation on the indole moiety of the molecule. M3 was also identified as a product derived from hydroxylation, but the structure of this metabolite was not identified because of the lack of a reference standard. M2, M4, and M6 were identified as the products derived from O-demethylation. M2, 6-desmethyl- BPR0L075, was the major metabolite formed by the liver micro- somes of the four Species. No qualitative Species Difference in the metabolism of BPR0L075 was observed. There was quantitative Species Difference in the metabolism of BPR0L075 among the four Species. Whereas mouse and rat liver microsomes metabolized BPR0L075 predominantly via O-demethylation, dog liver micro- somes metabolized BPR0L075 by O-demethylation and hydroxyla- tion to about the same extent. The rank order of intrinsic clearance rates for the conversion of BPR0L075 to 6-desmethyl-BPR0L075 was mouse > rat > human > dog. Incubation of BPR0L075 with baculovirus-insect cell-expressed human cytochrome P450 (P450) isozymes showed that CYP1A2, 2C9, 2C19, 2D6, 2E1, and 3A4 all catalyzed the O-demethylation and hydroxylation of BPR0L075 but to a different degree. Among the six P450 isozymes tested, CYP1A2 and 2D6 were most active on catalyzing the metabolism of BPR0L075. CYP1A2 catalyzed mainly the formation of M1, M2, and M3. M2 was the predominant metabolite formed by CYP2D6.
Hiroshi Kayakiri - One of the best experts on this subject based on the ideXlab platform.
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a new series of highly potent non peptide bradykinin b2 receptor antagonists incorporating the 4 heteroarylquinoline framework improvement of aqueous solubility and new insights into Species Difference
Journal of Medicinal Chemistry, 2004Co-Authors: Yuki Sawada, Hiroshi Kayakiri, Yoshito Abe, Keisuke Imai, Tsuyoshi Mizutani, Noriaki Inamura, Masayuki Asano, Ichiro Aramori, Chie Hatori, Akira KatayamaAbstract:Introduction of nitrogen-containing heteroaromatic groups at the 4-position of the quinoline moiety of our non-peptide B2 receptor antagonists resulted in enhancing binding affinities for the human B2 receptor and reducing binding affinities for the guinea pig one, providing new structural insights into Species Difference. A CoMFA study focused on the diversity of the quinoline moiety afforded correlative and predictive QSAR models of binding for the human B2 receptor but not for the guinea pig one. A series of 4-(1-imidazolyl)quinoline derivatives could be dissolved in a 5% aqueous solution of citric acid up to a concentration of 10 mg/mL. A representative compound 48a inhibited the specific binding of [3H]BK to the cloned human B2 receptor expressed in Chinese hamster ovary cells with an IC50 value of 0.26 nM and significantly inhibited BK-induced bronchoconstriction in guinea pigs even at 1 μg/kg by intravenous administration.
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a new series of highly potent non peptide bradykinin b2 receptor antagonists incorporating the 4 heteroarylquinoline framework improvement of aqueous solubility and new insights into Species Difference
Journal of Medicinal Chemistry, 2004Co-Authors: Yuki Sawada, Hiroshi Kayakiri, Yoshito Abe, Keisuke Imai, Tsuyoshi Mizutani, Noriaki Inamura, Masayuki Asano, Ichiro Aramori, Chie Hatori, Akira KatayamaAbstract:Introduction of nitrogen-containing heteroaromatic groups at the 4-position of the quinoline moiety of our non-peptide B2 receptor antagonists resulted in enhancing binding affinities for the human...
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a novel class of orally active non peptide bradykinin b2 receptor antagonists 2 overcoming the Species Difference between guinea pig and man
Journal of Medicinal Chemistry, 1998Co-Authors: Yoshito Abe, Yuki Sawada, Hiroshi Kayakiri, Noriaki Inamura, Masayuki Asano, Chie Hatori, Shigeki Satoh, Takayuki Inoue, Hiroe Sawai, Teruo OkuAbstract:Recently we reported the identification of a series of 8-[[3-(N-acylglycyl-N-methylamino)-2, 6-dichlorobenzyl]oxy]-3-halo-2-methylimidazo[1,2-a]pyridines as the first orally active non-peptide bradykinin (BK) B2 receptor antagonists (1-3). These compounds inhibited the specific binding of [3H]BK to guinea pig ileum membrane preparations expressing B2 receptors with nanomolar IC50's and also displayed in vivo functional antagonistic activities against BK-induced bronchoconstriction in guinea pigs at 1 mg/kg by oral administration. However, it was found that their affinities for the B2 receptors in human A-431 cells (human epidermoid carcinoma) were much lower. Intensive modifications of the terminal substituents at the glycine moiety elucidated the structure-activity relationships (SAR) for human B2 receptors, leading to an extended basic framework which incorporated a novel key pharmacophore. Thus, we overcame the Species Difference and identified the first clinical candidate 18c (FR167344) with IC50's of 0.66 and 1.4 nM for guinea pig ileum and human A-431 cells, respectively. This compound displayed in vivo functional antagonistic activity against BK-induced bronchoconstriction in guinea pigs with an ED50 value of 0.17 mg/kg by oral administration. This novel non-peptide B2 antagonist is extremely potent both in vitro and in vivo by oral administration and is expected to be the first member of a new class of drug for the treatment of various inflammatory diseases.
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a novel class of orally active non peptide bradykinin b2 receptor antagonists 3 discovering bioisosteres of the imidazo 1 2 a pyridine moiety
Journal of Medicinal Chemistry, 1998Co-Authors: Yoshito Abe, Yuki Sawada, Hiroshi Kayakiri, Noriaki Inamura, Masayuki Asano, Ichiro Aramori, Chie Hatori, Shigeki Satoh, Takayuki Inoue, Hiroe SawaiAbstract:Recently we reported on overcoming the Species Difference of our first orally active non-peptide bradykinin (BK) B2 receptor antagonists, incorporating an 8-[[3-(N-acylglycyl-N-methylamino)-2,6-dichlorobenzyl]oxy]-3-halo-2-methylimidazo[1,2-a]pyridine skeleton, leading to identification of the first clinical candidate 4a (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-a]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-a]pyridine ring and the 2,6-dichlorobenzyl moiety, leading to the discovery of our second clinical candidate 87b (FR173657) which inhibited the specific binding of [3H]BK to recombinant human B2 receptors expressed in Chinese hamster ovary (CHO) cells and guinea pig ileum membrane preparations expressing B2 receptors with IC50'...
Chie Hatori - One of the best experts on this subject based on the ideXlab platform.
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a new series of highly potent non peptide bradykinin b2 receptor antagonists incorporating the 4 heteroarylquinoline framework improvement of aqueous solubility and new insights into Species Difference
Journal of Medicinal Chemistry, 2004Co-Authors: Yuki Sawada, Hiroshi Kayakiri, Yoshito Abe, Keisuke Imai, Tsuyoshi Mizutani, Noriaki Inamura, Masayuki Asano, Ichiro Aramori, Chie Hatori, Akira KatayamaAbstract:Introduction of nitrogen-containing heteroaromatic groups at the 4-position of the quinoline moiety of our non-peptide B2 receptor antagonists resulted in enhancing binding affinities for the human B2 receptor and reducing binding affinities for the guinea pig one, providing new structural insights into Species Difference. A CoMFA study focused on the diversity of the quinoline moiety afforded correlative and predictive QSAR models of binding for the human B2 receptor but not for the guinea pig one. A series of 4-(1-imidazolyl)quinoline derivatives could be dissolved in a 5% aqueous solution of citric acid up to a concentration of 10 mg/mL. A representative compound 48a inhibited the specific binding of [3H]BK to the cloned human B2 receptor expressed in Chinese hamster ovary cells with an IC50 value of 0.26 nM and significantly inhibited BK-induced bronchoconstriction in guinea pigs even at 1 μg/kg by intravenous administration.
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a new series of highly potent non peptide bradykinin b2 receptor antagonists incorporating the 4 heteroarylquinoline framework improvement of aqueous solubility and new insights into Species Difference
Journal of Medicinal Chemistry, 2004Co-Authors: Yuki Sawada, Hiroshi Kayakiri, Yoshito Abe, Keisuke Imai, Tsuyoshi Mizutani, Noriaki Inamura, Masayuki Asano, Ichiro Aramori, Chie Hatori, Akira KatayamaAbstract:Introduction of nitrogen-containing heteroaromatic groups at the 4-position of the quinoline moiety of our non-peptide B2 receptor antagonists resulted in enhancing binding affinities for the human...
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a novel class of orally active non peptide bradykinin b2 receptor antagonists 2 overcoming the Species Difference between guinea pig and man
Journal of Medicinal Chemistry, 1998Co-Authors: Yoshito Abe, Yuki Sawada, Hiroshi Kayakiri, Noriaki Inamura, Masayuki Asano, Chie Hatori, Shigeki Satoh, Takayuki Inoue, Hiroe Sawai, Teruo OkuAbstract:Recently we reported the identification of a series of 8-[[3-(N-acylglycyl-N-methylamino)-2, 6-dichlorobenzyl]oxy]-3-halo-2-methylimidazo[1,2-a]pyridines as the first orally active non-peptide bradykinin (BK) B2 receptor antagonists (1-3). These compounds inhibited the specific binding of [3H]BK to guinea pig ileum membrane preparations expressing B2 receptors with nanomolar IC50's and also displayed in vivo functional antagonistic activities against BK-induced bronchoconstriction in guinea pigs at 1 mg/kg by oral administration. However, it was found that their affinities for the B2 receptors in human A-431 cells (human epidermoid carcinoma) were much lower. Intensive modifications of the terminal substituents at the glycine moiety elucidated the structure-activity relationships (SAR) for human B2 receptors, leading to an extended basic framework which incorporated a novel key pharmacophore. Thus, we overcame the Species Difference and identified the first clinical candidate 18c (FR167344) with IC50's of 0.66 and 1.4 nM for guinea pig ileum and human A-431 cells, respectively. This compound displayed in vivo functional antagonistic activity against BK-induced bronchoconstriction in guinea pigs with an ED50 value of 0.17 mg/kg by oral administration. This novel non-peptide B2 antagonist is extremely potent both in vitro and in vivo by oral administration and is expected to be the first member of a new class of drug for the treatment of various inflammatory diseases.
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a novel class of orally active non peptide bradykinin b2 receptor antagonists 3 discovering bioisosteres of the imidazo 1 2 a pyridine moiety
Journal of Medicinal Chemistry, 1998Co-Authors: Yoshito Abe, Yuki Sawada, Hiroshi Kayakiri, Noriaki Inamura, Masayuki Asano, Ichiro Aramori, Chie Hatori, Shigeki Satoh, Takayuki Inoue, Hiroe SawaiAbstract:Recently we reported on overcoming the Species Difference of our first orally active non-peptide bradykinin (BK) B2 receptor antagonists, incorporating an 8-[[3-(N-acylglycyl-N-methylamino)-2,6-dichlorobenzyl]oxy]-3-halo-2-methylimidazo[1,2-a]pyridine skeleton, leading to identification of the first clinical candidate 4a (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-a]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-a]pyridine ring and the 2,6-dichlorobenzyl moiety, leading to the discovery of our second clinical candidate 87b (FR173657) which inhibited the specific binding of [3H]BK to recombinant human B2 receptors expressed in Chinese hamster ovary (CHO) cells and guinea pig ileum membrane preparations expressing B2 receptors with IC50'...
