Pyrazolo[4,3-d]pyrimidine Derivatives as a Novel Hypoxia-Inducible Factor Prolyl Hydroxylase Domain Inhibitor for the Treatment of Anemia
| Autor: | Atsushi Kawata, Yoko Takada, Yoshiyuki Komatsu, Rikiya Ohashi, Takashi Goi, Asami Umeda, Okimasa Okada, Jun Murakami, Koichi Fukase, Sugahara Masakatsu, Tatsuo Nakajima, Tomoko Watanabe, Shuhei Yamakoshi |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Pyrimidine
010405 organic chemistry Protein subunit Organic Chemistry Pharmacology 01 natural sciences Biochemistry Pyrazolopyrimidine 0104 chemical sciences Bioavailability 010404 medicinal & biomolecular chemistry chemistry.chemical_compound chemistry Hypoxia-inducible factors Erythropoietin Oral administration hemic and lymphatic diseases Drug Discovery medicine Moiety medicine.drug |
| Zdroj: | ACS Medicinal Chemistry Letters. 11:1416-1420 |
| ISSN: | 1948-5875 |
| DOI: | 10.1021/acsmedchemlett.0c00108 |
| Popis: | Inhibition of hypoxia-inducible factor prolyl hydroxylase domain (HIF-PHD) promotes erythropoietin (EPO) production by stabilizing the HIFα subunit. Thieno[2,3-d]pyrimidine 8 identified based on X-ray crystal structure analysis was optimized to lead to the discovery of pyrazolo[4,3-d]pyrimidine 13 as the lead compound of orally bioavailable HIF-PHD inhibitors. Conversion of the benzyl moiety in 13 gave pyrazolopyrimidine 19 with high solubility and bioavailability, which increased hemoglobin levels in anemic model rats after repeated oral administration. It was shown that pyrazolo[4,3-d]pyrimidine derivatives are promising therapeutic agents for renal anemia through the inhibition of HIF-PHD. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|