Discovery and SAR of a novel series of Natriuretic Peptide Receptor-A (NPR-A) agonists |
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Authors: | Takehiko Iwaki Yuji Nakamura Taisaku Tanaka Yasuyuki Ogawa Osamu Iwamoto Yoshihiko Okamura Yumi Kawase Mayumi Furuya Yoshiaki Oyama Takahiro Nagayama |
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Institution: | 1. Asubio Pharma Co. Ltd, 6-4-3, Minatojima-Minamimachi, Chuo-ku, Kobe 650-0047, Japan;2. Daiichi Sankyo Co. Ltd, 1-2-58, Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan |
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Abstract: | Novel thienopyrimidine compounds 2 and 3 were discovered from high-throughput screening as Natriuretic Peptide Receptor A (NPR-A) agonists. Scaffold hopping of a thienopyrimidine ring to a quinazoline ring, introduction of the basic functional group and optimization of the substituent on the 6-position of the benzene ring of quinazoline led to improved agonistic activity. We discovered compound 48, which showed potent agonistic activity for NPR-A with an EC50 value of 0.073 μM, indicating 350-fold potency compared to the hit compound 3. |
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Keywords: | Natriuretic Peptide Receptor A Agonist Scaffold hopping Thienopyrimidine derivatives Quinazoline derivatives |
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