化学
生物利用度
利钠肽
药代动力学
心力衰竭
药理学
内科学
等电点
脂肪酸
射血分数
肽
代谢稳定性
生物活性
射血分数保留的心力衰竭
心脏病学
溶解度
体外
肽类激素
皮下注射
心钠素
作者
Anne Louise Bank Kodal,Jonathan A. Ewald,Christian Poulsen,Mathilde Frederikke Bjørn Bonde,Jeppe Kirchhoff,Svend Poulsen,Heidi S. Schultz,Karen‐Margrethe Pedersen,L Martis,Rikke Kaae Kirk,K. Madsen,Steen Sørensen,Lene Alifrangis,Jonas Wilbs,Peter Madsen,Trine Pagh Ludvigsen,T. Pedersen,Simone Fulle,Christian W. Tornøe,Nina Nørager
标识
DOI:10.1021/acs.jmedchem.5c02467
摘要
C-type natriuretic peptide (CNP) has therapeutic potential in heart failure with preserved ejection fraction (HFpEF) due to its broad range of beneficial effects on cardiovascular structure and function. This study presents the design of a CNP analogue (65) for once-weekly subcutaneous administration. The design of 65 incorporated five strategic substitutions and an engineered fatty acid protractor to enhance the chemical stability, improve the pharmacokinetics, and lower the isoelectric point (pI). Low pI was found to be essential for minimizing injection site reactions and improving subcutaneous bioavailability. 65 demonstrated a promising pharmacokinetic profile for once-weekly treatment and an improved bioavailability compared to high pI CNP analogs. Furthermore, 65 was engineered for solubility at pH 6.5 to enable stability in liquid formulation. In vivo assessments supported the therapeutic potential in HFpEF of fatty acid-derivatized low pI CNP analogues. 65 is currently under clinical investigation in Phase 1.
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