The Experts below are selected from a list of 1998 Experts worldwide ranked by ideXlab platform
Naoki Nishizawa - One of the best experts on this subject based on the ideXlab platform.
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a new class of pentapeptide Kiss1 Receptor agonists with hypothalamic pituitary gonadal axis activation
Bioorganic & Medicinal Chemistry Letters, 2019Co-Authors: Naoki Nishizawa, Yoshihiro Takatsu, Kimiko Nishibori, Taiji Asami, Shin-ichi Matsumoto, Masashi Yamaguchi, Atsuko Suzuki, Kazutaka Ushio, Yuji Shimizu, Masami KusakaAbstract:Abstract The kisspeptin (Kp, Kp-54, metastin)/Kiss1R system plays crucial roles in regulating the secretion of gonadotropin-releasing hormone. Continuous administration of nonapeptide Kp analogs caused plasma testosterone depletion, whereas bolus administration caused strong plasma testosterone elevation in male rats. To develop a new class of small peptide drugs, we focused on stepwise N-terminal truncation of Kp analogs and discovered potent pentapeptide analogs. Benzoyl-Phe-azaGly-Leu-Arg(Me)-Trp-NH2 (16) exhibited high agonist activity for Kiss1R and excellent metabolic stability in rat serum. A single injection of a 4-pyridyl analog (19) at the N-terminus of 16 into male Sprague Dawley rats caused a robust increase in plasma luteinizing hormone levels, but unlike continuous administration of nonapeptide Kp analogs, continuous administration of 19 maintained moderate testosterone levels in rats. These results indicated that small peptide drugs can be successfully developed for treating sex hormone deficiency.
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design and synthesis of an investigational nonapeptide Kiss1 Receptor Kiss1r agonist ac d tyr hydroxyproline hyp asn thr phe azagly leu arg me trp nh2 tak 448 with highly potent testosterone suppressive activity and excellent water solubility
Journal of Medicinal Chemistry, 2016Co-Authors: Naoki Nishizawa, Yoshihiro Takatsu, Satoshi Kumano, Hisanori Matsui, Shin-ichi Matsumoto, Masashi Yamaguchi, Atsushi Kiba, Junko Ban, Shunichirou Tsutsumi, Yukihiro IkedaAbstract:Metastin/kisspeptin is an endogenous ligand of Kiss1 Receptor (Kiss1R). Metastin and Kiss1R are suggested to play crucial roles in regulating the secretion of gonadotropin-releasing hormone (GnRH), and continuous administration of metastin derivatives attenuated the plasma testosterone levels in male rats. Our optimization studies of metastin derivatives led to the discovery of 1 (Ac-d-Tyr-d-Trp-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH2, TAK-683), which suppressed plasma testosterone in rats at lower doses than those of leuprolide. Although 1 possessed extremely potent pharmacological activity, 20 mg/mL aqueous solution of 1 has a gel formation property. In order to improve this physicochemical property, we substituted d-Trp at position 47 with a variety of amino acids; we identified that substitution with cyclic amino acids, which could change peptide conformation, retained its potency. Especially, analogue 24 (TAK-448) with trans-4-hydroxyproline (Hyp) at position 47 showed not only superior pharmacologica...
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Design and Synthesis of an Investigational Nonapeptide Kiss1 Receptor (Kiss1R) Agonist, Ac‑d‑Tyr-Hydroxyproline (Hyp)-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH2 (TAK-448), with Highly Potent Testosterone-Suppressive Activity and Excellent Water Solubilit
2016Co-Authors: Naoki Nishizawa, Yoshihiro Takatsu, Satoshi Kumano, Hisanori Matsui, Shin-ichi Matsumoto, Masashi Yamaguchi, Atsushi Kiba, Junko Ban, Shunichirou Tsutsumi, Yukihiro IkedaAbstract:Metastin/kisspeptin is an endogenous ligand of Kiss1 Receptor (Kiss1R). Metastin and Kiss1R are suggested to play crucial roles in regulating the secretion of gonadotropin-releasing hormone (GnRH), and continuous administration of metastin derivatives attenuated the plasma testosterone levels in male rats. Our optimization studies of metastin derivatives led to the discovery of 1 (Ac-d-Tyr-d-Trp-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH2, TAK-683), which suppressed plasma testosterone in rats at lower doses than those of leuprolide. Although 1 possessed extremely potent pharmacological activity, 20 mg/mL aqueous solution of 1 has a gel formation property. In order to improve this physicochemical property, we substituted d-Trp at position 47 with a variety of amino acids; we identified that substitution with cyclic amino acids, which could change peptide conformation, retained its potency. Especially, analogue 24 (TAK-448) with trans-4-hydroxyproline (Hyp) at position 47 showed not only superior pharmacological activity to 1 but also excellent water solubility. Furthermore, 20 mg/mL aqueous solution of 24 did not show gel formation up to 5 days
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physicochemically and pharmacokinetically stable nonapeptide Kiss1 Receptor agonists with highly potent testosterone suppressive activity
Journal of Medicinal Chemistry, 2014Co-Authors: Taiji Asami, Yoshihiro Takatsu, Kimiko Nishibori, Naoki Nishizawa, Hisanori Matsui, Masaharu Nakayama, Atsuko Suzuki, Atsushi Kiba, Michiko Terada, Junko BanAbstract:Modifications of metastin(45–54) produced peptide analogues with higher metabolic stability than metastin(45–54). N-terminally truncated nonapeptide 4 ([d-Tyr46,d-Pya(4)47,azaGly51,Arg(Me)53]metastin(46–54)) is a representative compound with both potent agonistic activity and metabolic stability. Although 4 had more potent testosterone-suppressant activity than metastin, it possessed physicochemical instability at pH 7 and insufficient in vivo activity. Instability at pH 7 was dependent upon Asn48 and Ser49; substitution of Ser49 with Thr49 reduced this instability and maintained Kiss1 Receptor agonistic activity. Furthermore, [d-Tyr46,d-Trp47,Thr49,azaGly51,Arg(Me)53,Trp54]metastin(46–54) (14) showed 2-fold greater [Ca2+]i-mobilizing activity than metastin(45–54) and an apparent increase in physicochemical stability. N-terminal acetylation of 14 resulted in the most potent analogue, 22 (Ac-[d-Tyr46,d-Trp47,Thr49,azaGly51,Arg(Me)53,Trp54]metastin(46–54)). With continuous administration, 22 possessed 10–50...
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Physicochemically and Pharmacokinetically Stable Nonapeptide Kiss1 Receptor Agonists with Highly Potent Testosterone-Suppressive Activity
2014Co-Authors: Taiji Asami, Yoshihiro Takatsu, Kimiko Nishibori, Naoki Nishizawa, Hisanori Matsui, Masaharu Nakayama, Atsuko Suzuki, Atsushi Kiba, Michiko Terada, Junko BanAbstract:Modifications of metastin(45–54) produced peptide analogues with higher metabolic stability than metastin(45–54). N-terminally truncated nonapeptide 4 ([d-Tyr46,d-Pya(4)47,azaGly51,Arg(Me)53]metastin(46–54)) is a representative compound with both potent agonistic activity and metabolic stability. Although 4 had more potent testosterone-suppressant activity than metastin, it possessed physicochemical instability at pH 7 and insufficient in vivo activity. Instability at pH 7 was dependent upon Asn48 and Ser49; substitution of Ser49 with Thr49 reduced this instability and maintained Kiss1 Receptor agonistic activity. Furthermore, [d-Tyr46,d-Trp47,Thr49,azaGly51,Arg(Me)53,Trp54]metastin(46–54) (14) showed 2-fold greater [Ca2+]i-mobilizing activity than metastin(45–54) and an apparent increase in physicochemical stability. N-terminal acetylation of 14 resulted in the most potent analogue, 22 (Ac-[d-Tyr46,d-Trp47,Thr49,azaGly51,Arg(Me)53,Trp54]metastin(46–54)). With continuous administration, 22 possessed 10–50-fold more potent testosterone-suppressive activity in rats than 4. These results suggested that a controlled release of short-length Kiss1 Receptor agonists can suppress the hypothalamic–pituitary–gonadal axis and reduce testosterone levels. Compound 22 was selected for further preclinical evaluation for hormone-dependent diseases
Yoshihiro Takatsu - One of the best experts on this subject based on the ideXlab platform.
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a new class of pentapeptide Kiss1 Receptor agonists with hypothalamic pituitary gonadal axis activation
Bioorganic & Medicinal Chemistry Letters, 2019Co-Authors: Naoki Nishizawa, Yoshihiro Takatsu, Kimiko Nishibori, Taiji Asami, Shin-ichi Matsumoto, Masashi Yamaguchi, Atsuko Suzuki, Kazutaka Ushio, Yuji Shimizu, Masami KusakaAbstract:Abstract The kisspeptin (Kp, Kp-54, metastin)/Kiss1R system plays crucial roles in regulating the secretion of gonadotropin-releasing hormone. Continuous administration of nonapeptide Kp analogs caused plasma testosterone depletion, whereas bolus administration caused strong plasma testosterone elevation in male rats. To develop a new class of small peptide drugs, we focused on stepwise N-terminal truncation of Kp analogs and discovered potent pentapeptide analogs. Benzoyl-Phe-azaGly-Leu-Arg(Me)-Trp-NH2 (16) exhibited high agonist activity for Kiss1R and excellent metabolic stability in rat serum. A single injection of a 4-pyridyl analog (19) at the N-terminus of 16 into male Sprague Dawley rats caused a robust increase in plasma luteinizing hormone levels, but unlike continuous administration of nonapeptide Kp analogs, continuous administration of 19 maintained moderate testosterone levels in rats. These results indicated that small peptide drugs can be successfully developed for treating sex hormone deficiency.
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design and synthesis of an investigational nonapeptide Kiss1 Receptor Kiss1r agonist ac d tyr hydroxyproline hyp asn thr phe azagly leu arg me trp nh2 tak 448 with highly potent testosterone suppressive activity and excellent water solubility
Journal of Medicinal Chemistry, 2016Co-Authors: Naoki Nishizawa, Yoshihiro Takatsu, Satoshi Kumano, Hisanori Matsui, Shin-ichi Matsumoto, Masashi Yamaguchi, Atsushi Kiba, Junko Ban, Shunichirou Tsutsumi, Yukihiro IkedaAbstract:Metastin/kisspeptin is an endogenous ligand of Kiss1 Receptor (Kiss1R). Metastin and Kiss1R are suggested to play crucial roles in regulating the secretion of gonadotropin-releasing hormone (GnRH), and continuous administration of metastin derivatives attenuated the plasma testosterone levels in male rats. Our optimization studies of metastin derivatives led to the discovery of 1 (Ac-d-Tyr-d-Trp-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH2, TAK-683), which suppressed plasma testosterone in rats at lower doses than those of leuprolide. Although 1 possessed extremely potent pharmacological activity, 20 mg/mL aqueous solution of 1 has a gel formation property. In order to improve this physicochemical property, we substituted d-Trp at position 47 with a variety of amino acids; we identified that substitution with cyclic amino acids, which could change peptide conformation, retained its potency. Especially, analogue 24 (TAK-448) with trans-4-hydroxyproline (Hyp) at position 47 showed not only superior pharmacologica...
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Design and Synthesis of an Investigational Nonapeptide Kiss1 Receptor (Kiss1R) Agonist, Ac‑d‑Tyr-Hydroxyproline (Hyp)-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH2 (TAK-448), with Highly Potent Testosterone-Suppressive Activity and Excellent Water Solubilit
2016Co-Authors: Naoki Nishizawa, Yoshihiro Takatsu, Satoshi Kumano, Hisanori Matsui, Shin-ichi Matsumoto, Masashi Yamaguchi, Atsushi Kiba, Junko Ban, Shunichirou Tsutsumi, Yukihiro IkedaAbstract:Metastin/kisspeptin is an endogenous ligand of Kiss1 Receptor (Kiss1R). Metastin and Kiss1R are suggested to play crucial roles in regulating the secretion of gonadotropin-releasing hormone (GnRH), and continuous administration of metastin derivatives attenuated the plasma testosterone levels in male rats. Our optimization studies of metastin derivatives led to the discovery of 1 (Ac-d-Tyr-d-Trp-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH2, TAK-683), which suppressed plasma testosterone in rats at lower doses than those of leuprolide. Although 1 possessed extremely potent pharmacological activity, 20 mg/mL aqueous solution of 1 has a gel formation property. In order to improve this physicochemical property, we substituted d-Trp at position 47 with a variety of amino acids; we identified that substitution with cyclic amino acids, which could change peptide conformation, retained its potency. Especially, analogue 24 (TAK-448) with trans-4-hydroxyproline (Hyp) at position 47 showed not only superior pharmacological activity to 1 but also excellent water solubility. Furthermore, 20 mg/mL aqueous solution of 24 did not show gel formation up to 5 days
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physicochemically and pharmacokinetically stable nonapeptide Kiss1 Receptor agonists with highly potent testosterone suppressive activity
Journal of Medicinal Chemistry, 2014Co-Authors: Taiji Asami, Yoshihiro Takatsu, Kimiko Nishibori, Naoki Nishizawa, Hisanori Matsui, Masaharu Nakayama, Atsuko Suzuki, Atsushi Kiba, Michiko Terada, Junko BanAbstract:Modifications of metastin(45–54) produced peptide analogues with higher metabolic stability than metastin(45–54). N-terminally truncated nonapeptide 4 ([d-Tyr46,d-Pya(4)47,azaGly51,Arg(Me)53]metastin(46–54)) is a representative compound with both potent agonistic activity and metabolic stability. Although 4 had more potent testosterone-suppressant activity than metastin, it possessed physicochemical instability at pH 7 and insufficient in vivo activity. Instability at pH 7 was dependent upon Asn48 and Ser49; substitution of Ser49 with Thr49 reduced this instability and maintained Kiss1 Receptor agonistic activity. Furthermore, [d-Tyr46,d-Trp47,Thr49,azaGly51,Arg(Me)53,Trp54]metastin(46–54) (14) showed 2-fold greater [Ca2+]i-mobilizing activity than metastin(45–54) and an apparent increase in physicochemical stability. N-terminal acetylation of 14 resulted in the most potent analogue, 22 (Ac-[d-Tyr46,d-Trp47,Thr49,azaGly51,Arg(Me)53,Trp54]metastin(46–54)). With continuous administration, 22 possessed 10–50...
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Physicochemically and Pharmacokinetically Stable Nonapeptide Kiss1 Receptor Agonists with Highly Potent Testosterone-Suppressive Activity
2014Co-Authors: Taiji Asami, Yoshihiro Takatsu, Kimiko Nishibori, Naoki Nishizawa, Hisanori Matsui, Masaharu Nakayama, Atsuko Suzuki, Atsushi Kiba, Michiko Terada, Junko BanAbstract:Modifications of metastin(45–54) produced peptide analogues with higher metabolic stability than metastin(45–54). N-terminally truncated nonapeptide 4 ([d-Tyr46,d-Pya(4)47,azaGly51,Arg(Me)53]metastin(46–54)) is a representative compound with both potent agonistic activity and metabolic stability. Although 4 had more potent testosterone-suppressant activity than metastin, it possessed physicochemical instability at pH 7 and insufficient in vivo activity. Instability at pH 7 was dependent upon Asn48 and Ser49; substitution of Ser49 with Thr49 reduced this instability and maintained Kiss1 Receptor agonistic activity. Furthermore, [d-Tyr46,d-Trp47,Thr49,azaGly51,Arg(Me)53,Trp54]metastin(46–54) (14) showed 2-fold greater [Ca2+]i-mobilizing activity than metastin(45–54) and an apparent increase in physicochemical stability. N-terminal acetylation of 14 resulted in the most potent analogue, 22 (Ac-[d-Tyr46,d-Trp47,Thr49,azaGly51,Arg(Me)53,Trp54]metastin(46–54)). With continuous administration, 22 possessed 10–50-fold more potent testosterone-suppressive activity in rats than 4. These results suggested that a controlled release of short-length Kiss1 Receptor agonists can suppress the hypothalamic–pituitary–gonadal axis and reduce testosterone levels. Compound 22 was selected for further preclinical evaluation for hormone-dependent diseases
Junko Ban - One of the best experts on this subject based on the ideXlab platform.
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design and synthesis of an investigational nonapeptide Kiss1 Receptor Kiss1r agonist ac d tyr hydroxyproline hyp asn thr phe azagly leu arg me trp nh2 tak 448 with highly potent testosterone suppressive activity and excellent water solubility
Journal of Medicinal Chemistry, 2016Co-Authors: Naoki Nishizawa, Yoshihiro Takatsu, Satoshi Kumano, Hisanori Matsui, Shin-ichi Matsumoto, Masashi Yamaguchi, Atsushi Kiba, Junko Ban, Shunichirou Tsutsumi, Yukihiro IkedaAbstract:Metastin/kisspeptin is an endogenous ligand of Kiss1 Receptor (Kiss1R). Metastin and Kiss1R are suggested to play crucial roles in regulating the secretion of gonadotropin-releasing hormone (GnRH), and continuous administration of metastin derivatives attenuated the plasma testosterone levels in male rats. Our optimization studies of metastin derivatives led to the discovery of 1 (Ac-d-Tyr-d-Trp-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH2, TAK-683), which suppressed plasma testosterone in rats at lower doses than those of leuprolide. Although 1 possessed extremely potent pharmacological activity, 20 mg/mL aqueous solution of 1 has a gel formation property. In order to improve this physicochemical property, we substituted d-Trp at position 47 with a variety of amino acids; we identified that substitution with cyclic amino acids, which could change peptide conformation, retained its potency. Especially, analogue 24 (TAK-448) with trans-4-hydroxyproline (Hyp) at position 47 showed not only superior pharmacologica...
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Design and Synthesis of an Investigational Nonapeptide Kiss1 Receptor (Kiss1R) Agonist, Ac‑d‑Tyr-Hydroxyproline (Hyp)-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH2 (TAK-448), with Highly Potent Testosterone-Suppressive Activity and Excellent Water Solubilit
2016Co-Authors: Naoki Nishizawa, Yoshihiro Takatsu, Satoshi Kumano, Hisanori Matsui, Shin-ichi Matsumoto, Masashi Yamaguchi, Atsushi Kiba, Junko Ban, Shunichirou Tsutsumi, Yukihiro IkedaAbstract:Metastin/kisspeptin is an endogenous ligand of Kiss1 Receptor (Kiss1R). Metastin and Kiss1R are suggested to play crucial roles in regulating the secretion of gonadotropin-releasing hormone (GnRH), and continuous administration of metastin derivatives attenuated the plasma testosterone levels in male rats. Our optimization studies of metastin derivatives led to the discovery of 1 (Ac-d-Tyr-d-Trp-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH2, TAK-683), which suppressed plasma testosterone in rats at lower doses than those of leuprolide. Although 1 possessed extremely potent pharmacological activity, 20 mg/mL aqueous solution of 1 has a gel formation property. In order to improve this physicochemical property, we substituted d-Trp at position 47 with a variety of amino acids; we identified that substitution with cyclic amino acids, which could change peptide conformation, retained its potency. Especially, analogue 24 (TAK-448) with trans-4-hydroxyproline (Hyp) at position 47 showed not only superior pharmacological activity to 1 but also excellent water solubility. Furthermore, 20 mg/mL aqueous solution of 24 did not show gel formation up to 5 days
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physicochemically and pharmacokinetically stable nonapeptide Kiss1 Receptor agonists with highly potent testosterone suppressive activity
Journal of Medicinal Chemistry, 2014Co-Authors: Taiji Asami, Yoshihiro Takatsu, Kimiko Nishibori, Naoki Nishizawa, Hisanori Matsui, Masaharu Nakayama, Atsuko Suzuki, Atsushi Kiba, Michiko Terada, Junko BanAbstract:Modifications of metastin(45–54) produced peptide analogues with higher metabolic stability than metastin(45–54). N-terminally truncated nonapeptide 4 ([d-Tyr46,d-Pya(4)47,azaGly51,Arg(Me)53]metastin(46–54)) is a representative compound with both potent agonistic activity and metabolic stability. Although 4 had more potent testosterone-suppressant activity than metastin, it possessed physicochemical instability at pH 7 and insufficient in vivo activity. Instability at pH 7 was dependent upon Asn48 and Ser49; substitution of Ser49 with Thr49 reduced this instability and maintained Kiss1 Receptor agonistic activity. Furthermore, [d-Tyr46,d-Trp47,Thr49,azaGly51,Arg(Me)53,Trp54]metastin(46–54) (14) showed 2-fold greater [Ca2+]i-mobilizing activity than metastin(45–54) and an apparent increase in physicochemical stability. N-terminal acetylation of 14 resulted in the most potent analogue, 22 (Ac-[d-Tyr46,d-Trp47,Thr49,azaGly51,Arg(Me)53,Trp54]metastin(46–54)). With continuous administration, 22 possessed 10–50...
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Physicochemically and Pharmacokinetically Stable Nonapeptide Kiss1 Receptor Agonists with Highly Potent Testosterone-Suppressive Activity
2014Co-Authors: Taiji Asami, Yoshihiro Takatsu, Kimiko Nishibori, Naoki Nishizawa, Hisanori Matsui, Masaharu Nakayama, Atsuko Suzuki, Atsushi Kiba, Michiko Terada, Junko BanAbstract:Modifications of metastin(45–54) produced peptide analogues with higher metabolic stability than metastin(45–54). N-terminally truncated nonapeptide 4 ([d-Tyr46,d-Pya(4)47,azaGly51,Arg(Me)53]metastin(46–54)) is a representative compound with both potent agonistic activity and metabolic stability. Although 4 had more potent testosterone-suppressant activity than metastin, it possessed physicochemical instability at pH 7 and insufficient in vivo activity. Instability at pH 7 was dependent upon Asn48 and Ser49; substitution of Ser49 with Thr49 reduced this instability and maintained Kiss1 Receptor agonistic activity. Furthermore, [d-Tyr46,d-Trp47,Thr49,azaGly51,Arg(Me)53,Trp54]metastin(46–54) (14) showed 2-fold greater [Ca2+]i-mobilizing activity than metastin(45–54) and an apparent increase in physicochemical stability. N-terminal acetylation of 14 resulted in the most potent analogue, 22 (Ac-[d-Tyr46,d-Trp47,Thr49,azaGly51,Arg(Me)53,Trp54]metastin(46–54)). With continuous administration, 22 possessed 10–50-fold more potent testosterone-suppressive activity in rats than 4. These results suggested that a controlled release of short-length Kiss1 Receptor agonists can suppress the hypothalamic–pituitary–gonadal axis and reduce testosterone levels. Compound 22 was selected for further preclinical evaluation for hormone-dependent diseases
Yukihiro Ikeda - One of the best experts on this subject based on the ideXlab platform.
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design and synthesis of an investigational nonapeptide Kiss1 Receptor Kiss1r agonist ac d tyr hydroxyproline hyp asn thr phe azagly leu arg me trp nh2 tak 448 with highly potent testosterone suppressive activity and excellent water solubility
Journal of Medicinal Chemistry, 2016Co-Authors: Naoki Nishizawa, Yoshihiro Takatsu, Satoshi Kumano, Hisanori Matsui, Shin-ichi Matsumoto, Masashi Yamaguchi, Atsushi Kiba, Junko Ban, Shunichirou Tsutsumi, Yukihiro IkedaAbstract:Metastin/kisspeptin is an endogenous ligand of Kiss1 Receptor (Kiss1R). Metastin and Kiss1R are suggested to play crucial roles in regulating the secretion of gonadotropin-releasing hormone (GnRH), and continuous administration of metastin derivatives attenuated the plasma testosterone levels in male rats. Our optimization studies of metastin derivatives led to the discovery of 1 (Ac-d-Tyr-d-Trp-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH2, TAK-683), which suppressed plasma testosterone in rats at lower doses than those of leuprolide. Although 1 possessed extremely potent pharmacological activity, 20 mg/mL aqueous solution of 1 has a gel formation property. In order to improve this physicochemical property, we substituted d-Trp at position 47 with a variety of amino acids; we identified that substitution with cyclic amino acids, which could change peptide conformation, retained its potency. Especially, analogue 24 (TAK-448) with trans-4-hydroxyproline (Hyp) at position 47 showed not only superior pharmacologica...
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Design and Synthesis of an Investigational Nonapeptide Kiss1 Receptor (Kiss1R) Agonist, Ac‑d‑Tyr-Hydroxyproline (Hyp)-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH2 (TAK-448), with Highly Potent Testosterone-Suppressive Activity and Excellent Water Solubilit
2016Co-Authors: Naoki Nishizawa, Yoshihiro Takatsu, Satoshi Kumano, Hisanori Matsui, Shin-ichi Matsumoto, Masashi Yamaguchi, Atsushi Kiba, Junko Ban, Shunichirou Tsutsumi, Yukihiro IkedaAbstract:Metastin/kisspeptin is an endogenous ligand of Kiss1 Receptor (Kiss1R). Metastin and Kiss1R are suggested to play crucial roles in regulating the secretion of gonadotropin-releasing hormone (GnRH), and continuous administration of metastin derivatives attenuated the plasma testosterone levels in male rats. Our optimization studies of metastin derivatives led to the discovery of 1 (Ac-d-Tyr-d-Trp-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH2, TAK-683), which suppressed plasma testosterone in rats at lower doses than those of leuprolide. Although 1 possessed extremely potent pharmacological activity, 20 mg/mL aqueous solution of 1 has a gel formation property. In order to improve this physicochemical property, we substituted d-Trp at position 47 with a variety of amino acids; we identified that substitution with cyclic amino acids, which could change peptide conformation, retained its potency. Especially, analogue 24 (TAK-448) with trans-4-hydroxyproline (Hyp) at position 47 showed not only superior pharmacological activity to 1 but also excellent water solubility. Furthermore, 20 mg/mL aqueous solution of 24 did not show gel formation up to 5 days
Hisanori Matsui - One of the best experts on this subject based on the ideXlab platform.
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design and synthesis of an investigational nonapeptide Kiss1 Receptor Kiss1r agonist ac d tyr hydroxyproline hyp asn thr phe azagly leu arg me trp nh2 tak 448 with highly potent testosterone suppressive activity and excellent water solubility
Journal of Medicinal Chemistry, 2016Co-Authors: Naoki Nishizawa, Yoshihiro Takatsu, Satoshi Kumano, Hisanori Matsui, Shin-ichi Matsumoto, Masashi Yamaguchi, Atsushi Kiba, Junko Ban, Shunichirou Tsutsumi, Yukihiro IkedaAbstract:Metastin/kisspeptin is an endogenous ligand of Kiss1 Receptor (Kiss1R). Metastin and Kiss1R are suggested to play crucial roles in regulating the secretion of gonadotropin-releasing hormone (GnRH), and continuous administration of metastin derivatives attenuated the plasma testosterone levels in male rats. Our optimization studies of metastin derivatives led to the discovery of 1 (Ac-d-Tyr-d-Trp-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH2, TAK-683), which suppressed plasma testosterone in rats at lower doses than those of leuprolide. Although 1 possessed extremely potent pharmacological activity, 20 mg/mL aqueous solution of 1 has a gel formation property. In order to improve this physicochemical property, we substituted d-Trp at position 47 with a variety of amino acids; we identified that substitution with cyclic amino acids, which could change peptide conformation, retained its potency. Especially, analogue 24 (TAK-448) with trans-4-hydroxyproline (Hyp) at position 47 showed not only superior pharmacologica...
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Design and Synthesis of an Investigational Nonapeptide Kiss1 Receptor (Kiss1R) Agonist, Ac‑d‑Tyr-Hydroxyproline (Hyp)-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH2 (TAK-448), with Highly Potent Testosterone-Suppressive Activity and Excellent Water Solubilit
2016Co-Authors: Naoki Nishizawa, Yoshihiro Takatsu, Satoshi Kumano, Hisanori Matsui, Shin-ichi Matsumoto, Masashi Yamaguchi, Atsushi Kiba, Junko Ban, Shunichirou Tsutsumi, Yukihiro IkedaAbstract:Metastin/kisspeptin is an endogenous ligand of Kiss1 Receptor (Kiss1R). Metastin and Kiss1R are suggested to play crucial roles in regulating the secretion of gonadotropin-releasing hormone (GnRH), and continuous administration of metastin derivatives attenuated the plasma testosterone levels in male rats. Our optimization studies of metastin derivatives led to the discovery of 1 (Ac-d-Tyr-d-Trp-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH2, TAK-683), which suppressed plasma testosterone in rats at lower doses than those of leuprolide. Although 1 possessed extremely potent pharmacological activity, 20 mg/mL aqueous solution of 1 has a gel formation property. In order to improve this physicochemical property, we substituted d-Trp at position 47 with a variety of amino acids; we identified that substitution with cyclic amino acids, which could change peptide conformation, retained its potency. Especially, analogue 24 (TAK-448) with trans-4-hydroxyproline (Hyp) at position 47 showed not only superior pharmacological activity to 1 but also excellent water solubility. Furthermore, 20 mg/mL aqueous solution of 24 did not show gel formation up to 5 days
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physicochemically and pharmacokinetically stable nonapeptide Kiss1 Receptor agonists with highly potent testosterone suppressive activity
Journal of Medicinal Chemistry, 2014Co-Authors: Taiji Asami, Yoshihiro Takatsu, Kimiko Nishibori, Naoki Nishizawa, Hisanori Matsui, Masaharu Nakayama, Atsuko Suzuki, Atsushi Kiba, Michiko Terada, Junko BanAbstract:Modifications of metastin(45–54) produced peptide analogues with higher metabolic stability than metastin(45–54). N-terminally truncated nonapeptide 4 ([d-Tyr46,d-Pya(4)47,azaGly51,Arg(Me)53]metastin(46–54)) is a representative compound with both potent agonistic activity and metabolic stability. Although 4 had more potent testosterone-suppressant activity than metastin, it possessed physicochemical instability at pH 7 and insufficient in vivo activity. Instability at pH 7 was dependent upon Asn48 and Ser49; substitution of Ser49 with Thr49 reduced this instability and maintained Kiss1 Receptor agonistic activity. Furthermore, [d-Tyr46,d-Trp47,Thr49,azaGly51,Arg(Me)53,Trp54]metastin(46–54) (14) showed 2-fold greater [Ca2+]i-mobilizing activity than metastin(45–54) and an apparent increase in physicochemical stability. N-terminal acetylation of 14 resulted in the most potent analogue, 22 (Ac-[d-Tyr46,d-Trp47,Thr49,azaGly51,Arg(Me)53,Trp54]metastin(46–54)). With continuous administration, 22 possessed 10–50...
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Physicochemically and Pharmacokinetically Stable Nonapeptide Kiss1 Receptor Agonists with Highly Potent Testosterone-Suppressive Activity
2014Co-Authors: Taiji Asami, Yoshihiro Takatsu, Kimiko Nishibori, Naoki Nishizawa, Hisanori Matsui, Masaharu Nakayama, Atsuko Suzuki, Atsushi Kiba, Michiko Terada, Junko BanAbstract:Modifications of metastin(45–54) produced peptide analogues with higher metabolic stability than metastin(45–54). N-terminally truncated nonapeptide 4 ([d-Tyr46,d-Pya(4)47,azaGly51,Arg(Me)53]metastin(46–54)) is a representative compound with both potent agonistic activity and metabolic stability. Although 4 had more potent testosterone-suppressant activity than metastin, it possessed physicochemical instability at pH 7 and insufficient in vivo activity. Instability at pH 7 was dependent upon Asn48 and Ser49; substitution of Ser49 with Thr49 reduced this instability and maintained Kiss1 Receptor agonistic activity. Furthermore, [d-Tyr46,d-Trp47,Thr49,azaGly51,Arg(Me)53,Trp54]metastin(46–54) (14) showed 2-fold greater [Ca2+]i-mobilizing activity than metastin(45–54) and an apparent increase in physicochemical stability. N-terminal acetylation of 14 resulted in the most potent analogue, 22 (Ac-[d-Tyr46,d-Trp47,Thr49,azaGly51,Arg(Me)53,Trp54]metastin(46–54)). With continuous administration, 22 possessed 10–50-fold more potent testosterone-suppressive activity in rats than 4. These results suggested that a controlled release of short-length Kiss1 Receptor agonists can suppress the hypothalamic–pituitary–gonadal axis and reduce testosterone levels. Compound 22 was selected for further preclinical evaluation for hormone-dependent diseases
