The Experts below are selected from a list of 207 Experts worldwide ranked by ideXlab platform
Kenji Omori - One of the best experts on this subject based on the ideXlab platform.
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discovery of 2 e 2 7 fluoro 3 methylquinoxalin 2 yl vinyl 6 pyrrolidin 1 yl n tetrahydro 2h pyran 4 yl pyrimidin 4 amine hydrochloride as a highly selective pde10a inhibitor
Chemical & Pharmaceutical Bulletin, 2018Co-Authors: Yoichi Kadoh, Kenji Omori, Haruko Miyoshi, Takehiko Matsumura, Yoshihito Tanaka, Mitsuya Hongu, Mayumi Kimura, Kei Takedomi, Jun KoteraAbstract:Phosphodiesterase (PDE) 10A is a dual hydrolase of cAMP and cGMP and highly expressed in striatal medium spiny neurons. Inhibition of PDE10A modulates the activity of medium spiny neurons (MSN) via the regulation of cAMP and cGMP. Signal control of MSN is considered associated with psychotic symptoms. Therefore PDE10A inhibitor is expected as a therapeutic method for psychosis disease such as schizophrenia. Avanafil (1) is a PDE5 inhibitor (treatment for erectile dysfunction) discovered by our company. We paid attention to the homology of PDE10A and PDE5 and took advantage of PDE5 inhibitor library to discover PDE10A inhibitors, and found a series of compounds that exhibit higher potency for PDE10A than PDE5. We transformed the afforded derivatives, which had weak inhibitory activity against PDE10A, and discovered stilbene as a PDE10A inhibitor. Brain penetration of this compound was improved by further conversion of N-containing heterocycles and their substituents. The afforded dimethylaminopyrimidine was effective for rat conditioned avoidance response (CAR) test; however, it did not exhibit good brain penetration. We performed in-depth optimization focusing on substituents of the quinoxaline ring, and produced 3-methyl-7-fluoro quinoxaline. This compound was the most effective in rat CAR test due to its strong PDE10A inhibitory activity and good pharmacokinetics.
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the discovery of Avanafil for the treatment of erectile dysfunction a novel pyrimidine 5 carboxamide derivative as a potent and highly selective phosphodiesterase 5 inhibitor
Bioorganic & Medicinal Chemistry Letters, 2014Co-Authors: Toshiaki Sakamoto, Kenji Omori, Jun Kotera, Kotomi Fujishige, Yuichi Koga, Masataka Hikota, Kenji Matsuki, Michino Murakami, Kohei KikkawaAbstract:Abstract Novel pyrimidine-5-carboxamide derivatives bearing a 3-chloro-4-methoxybenzylamino group at the 4-position were identified as potent and highly selective phosphodiesterase 5 inhibitors. Among them, we successfully found 10j (Avanafil) which exhibited a potent relaxant effect on isolated rabbit cavernosum (EC30 = 2.1 nM) and a high isozyme selectivity.
Jun Kotera - One of the best experts on this subject based on the ideXlab platform.
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discovery of 2 e 2 7 fluoro 3 methylquinoxalin 2 yl vinyl 6 pyrrolidin 1 yl n tetrahydro 2h pyran 4 yl pyrimidin 4 amine hydrochloride as a highly selective pde10a inhibitor
Chemical & Pharmaceutical Bulletin, 2018Co-Authors: Yoichi Kadoh, Kenji Omori, Haruko Miyoshi, Takehiko Matsumura, Yoshihito Tanaka, Mitsuya Hongu, Mayumi Kimura, Kei Takedomi, Jun KoteraAbstract:Phosphodiesterase (PDE) 10A is a dual hydrolase of cAMP and cGMP and highly expressed in striatal medium spiny neurons. Inhibition of PDE10A modulates the activity of medium spiny neurons (MSN) via the regulation of cAMP and cGMP. Signal control of MSN is considered associated with psychotic symptoms. Therefore PDE10A inhibitor is expected as a therapeutic method for psychosis disease such as schizophrenia. Avanafil (1) is a PDE5 inhibitor (treatment for erectile dysfunction) discovered by our company. We paid attention to the homology of PDE10A and PDE5 and took advantage of PDE5 inhibitor library to discover PDE10A inhibitors, and found a series of compounds that exhibit higher potency for PDE10A than PDE5. We transformed the afforded derivatives, which had weak inhibitory activity against PDE10A, and discovered stilbene as a PDE10A inhibitor. Brain penetration of this compound was improved by further conversion of N-containing heterocycles and their substituents. The afforded dimethylaminopyrimidine was effective for rat conditioned avoidance response (CAR) test; however, it did not exhibit good brain penetration. We performed in-depth optimization focusing on substituents of the quinoxaline ring, and produced 3-methyl-7-fluoro quinoxaline. This compound was the most effective in rat CAR test due to its strong PDE10A inhibitory activity and good pharmacokinetics.
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the discovery of Avanafil for the treatment of erectile dysfunction a novel pyrimidine 5 carboxamide derivative as a potent and highly selective phosphodiesterase 5 inhibitor
Bioorganic & Medicinal Chemistry Letters, 2014Co-Authors: Toshiaki Sakamoto, Kenji Omori, Jun Kotera, Kotomi Fujishige, Yuichi Koga, Masataka Hikota, Kenji Matsuki, Michino Murakami, Kohei KikkawaAbstract:Abstract Novel pyrimidine-5-carboxamide derivatives bearing a 3-chloro-4-methoxybenzylamino group at the 4-position were identified as potent and highly selective phosphodiesterase 5 inhibitors. Among them, we successfully found 10j (Avanafil) which exhibited a potent relaxant effect on isolated rabbit cavernosum (EC30 = 2.1 nM) and a high isozyme selectivity.
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Avanafil a potent and highly selective phosphodiesterase 5 inhibitor for erectile dysfunction
The Journal of Urology, 2012Co-Authors: Jun Kotera, Hideki Mochida, Hirotaka Inoue, Tsunehisa Noto, Kotomi Fujishige, Takashi Sasaki, Tamaki Kobayashi, Koki Kojima, Shiyin Yee, Yasuhiro YamadaAbstract:Purpose: We investigated the in vitro inhibitory effects of Avanafil, a novel, potent inhibitor of phosphodiesterase-5, on 11 phosphodiesterases. We also studied its potentiation of penile tumescence in dogs.Materials and Methods: Phosphodiesterase assay was done with the 4 phosphodiesterase-5 inhibitors Avanafil, sildenafil, vardenafil and tadalafil using 11 phosphodiesterase isozymes. In anesthetized dogs the pelvic nerve was repeatedly stimulated to evoke tumescence. Intracavernous pressure was measured after Avanafil or sildenafil administration.Results: Avanafil specifically inhibited phosphodiesterase-5 activity at a 50% inhibitory concentration of 5.2 nM. Avanafil showed higher selectivity (121-fold) against phosphodiesterase-6 than sildenafil and vardenafil (16 to 21-fold) and showed excellent selectivity (greater than 10,000-fold) against phosphodiesterase-1 compared with sildenafil (375-fold). Avanafil also had higher selectivity against phosphodiesterase-11 than tadalafil (greater than 19,000 v...
Kotomi Fujishige - One of the best experts on this subject based on the ideXlab platform.
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the discovery of Avanafil for the treatment of erectile dysfunction a novel pyrimidine 5 carboxamide derivative as a potent and highly selective phosphodiesterase 5 inhibitor
Bioorganic & Medicinal Chemistry Letters, 2014Co-Authors: Toshiaki Sakamoto, Kenji Omori, Jun Kotera, Kotomi Fujishige, Yuichi Koga, Masataka Hikota, Kenji Matsuki, Michino Murakami, Kohei KikkawaAbstract:Abstract Novel pyrimidine-5-carboxamide derivatives bearing a 3-chloro-4-methoxybenzylamino group at the 4-position were identified as potent and highly selective phosphodiesterase 5 inhibitors. Among them, we successfully found 10j (Avanafil) which exhibited a potent relaxant effect on isolated rabbit cavernosum (EC30 = 2.1 nM) and a high isozyme selectivity.
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Avanafil a potent and highly selective phosphodiesterase 5 inhibitor for erectile dysfunction
The Journal of Urology, 2012Co-Authors: Jun Kotera, Hideki Mochida, Hirotaka Inoue, Tsunehisa Noto, Kotomi Fujishige, Takashi Sasaki, Tamaki Kobayashi, Koki Kojima, Shiyin Yee, Yasuhiro YamadaAbstract:Purpose: We investigated the in vitro inhibitory effects of Avanafil, a novel, potent inhibitor of phosphodiesterase-5, on 11 phosphodiesterases. We also studied its potentiation of penile tumescence in dogs.Materials and Methods: Phosphodiesterase assay was done with the 4 phosphodiesterase-5 inhibitors Avanafil, sildenafil, vardenafil and tadalafil using 11 phosphodiesterase isozymes. In anesthetized dogs the pelvic nerve was repeatedly stimulated to evoke tumescence. Intracavernous pressure was measured after Avanafil or sildenafil administration.Results: Avanafil specifically inhibited phosphodiesterase-5 activity at a 50% inhibitory concentration of 5.2 nM. Avanafil showed higher selectivity (121-fold) against phosphodiesterase-6 than sildenafil and vardenafil (16 to 21-fold) and showed excellent selectivity (greater than 10,000-fold) against phosphodiesterase-1 compared with sildenafil (375-fold). Avanafil also had higher selectivity against phosphodiesterase-11 than tadalafil (greater than 19,000 v...
Yasuhiro Yamada - One of the best experts on this subject based on the ideXlab platform.
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Avanafil a potent and highly selective phosphodiesterase 5 inhibitor for erectile dysfunction
The Journal of Urology, 2012Co-Authors: Jun Kotera, Hideki Mochida, Hirotaka Inoue, Tsunehisa Noto, Kotomi Fujishige, Takashi Sasaki, Tamaki Kobayashi, Koki Kojima, Shiyin Yee, Yasuhiro YamadaAbstract:Purpose: We investigated the in vitro inhibitory effects of Avanafil, a novel, potent inhibitor of phosphodiesterase-5, on 11 phosphodiesterases. We also studied its potentiation of penile tumescence in dogs.Materials and Methods: Phosphodiesterase assay was done with the 4 phosphodiesterase-5 inhibitors Avanafil, sildenafil, vardenafil and tadalafil using 11 phosphodiesterase isozymes. In anesthetized dogs the pelvic nerve was repeatedly stimulated to evoke tumescence. Intracavernous pressure was measured after Avanafil or sildenafil administration.Results: Avanafil specifically inhibited phosphodiesterase-5 activity at a 50% inhibitory concentration of 5.2 nM. Avanafil showed higher selectivity (121-fold) against phosphodiesterase-6 than sildenafil and vardenafil (16 to 21-fold) and showed excellent selectivity (greater than 10,000-fold) against phosphodiesterase-1 compared with sildenafil (375-fold). Avanafil also had higher selectivity against phosphodiesterase-11 than tadalafil (greater than 19,000 v...
Wesley W Day - One of the best experts on this subject based on the ideXlab platform.
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a phase 3 placebo controlled study of the safety and efficacy of Avanafil for the treatment of erectile dysfunction after nerve sparing radical prostatectomy
The Journal of Urology, 2013Co-Authors: John P Mulhall, Karen Didonato, Arthur L Burnett, Run Wang, Kevin T Mcvary, Judd W Moul, Charles H Bowden, Winnie Shih, Wesley W DayAbstract:Purpose: We evaluated the safety and efficacy of 100 and 200 mg Avanafil for the treatment of adult males with erectile dysfunction after bilateral nerve sparing radical prostatectomy.Materials and Methods: This was a double-blind, placebo controlled, parallel group, phase 3 study in males age 18 to 70 years with a history of erectile dysfunction of 6 months or more after bilateral nerve sparing radical prostatectomy. Patients were randomized to 100 or 200 mg Avanafil or placebo (taken 30 minutes before sexual activity) for 12 weeks. Primary end points included successful vaginal insertion (Sexual Encounter Profile [SEP] question 2), successful intercourse (SEP3) and change in score on the erectile function domain of the International Index of Erectile Function (IIEF-EF) questionnaire.Results: A total of 298 patients were randomized and 84.6% completed the study. At baseline 16.1% were age 65 years or older and 71.5% had severe erectile dysfunction (mean overall IIEF-EF domain score 9.2). After 12 weeks t...
