当前位置： SCI文献检索 > JOURNAL OF MEDICINAL CHEMISTRY期刊下所有文献 > Structure-Activity Relationships and Characterization of Highly Selective, Long-Acting, Peptide-Based Cholecystokinin 1 Receptor Agonists.

Structure-Activity Relationships and Characterization of Highly Selective, Long-Acting, Peptide-Based Cholecystokinin 1 Receptor Agonists.

Abstract：

:A group of peptide-based, long-acting, stable, highly selective cholecystokinin 1 receptor (CCK-1R) agonists with the potential to treat obesity has been identified and characterized, based on systematic investigation of synthetic CCK-8 analogues with N-terminal linkage to fatty acids. Sulfated Tyr in such compounds was stable in neutral buffer. CCK-1R selectivity was achieved mostly by introducing d- N-methyl-Asp instead of Asp at the penultimate position of CCK-8. Our compound 9 (NN9056) showed similar in vitro CCK-1R potency and CCK-1R affinity as CCK-8, very high selectivity for CCK-1R over the cholecystokinin 2 receptor (CCK-2R), strong reduction of food intake in lean pigs for up to 48 h after one subcutaneous injection without adverse effects, a plasma half-life of 113 h in minipigs after intravenous injection, and acceptable chemical stability in a neutral liquid formulation. In addition, we found a highly selective CCK-2R agonist by replacing Gly in a CCK-8 derivative with Glu.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Sensfuss U,Kruse T,Skyggebjerg RB,Uldam HK,Vestergaard B,Huus K,Vinther TN,Reinau ME,Schéele S,Clausen TR

doi

10.1021/acs.jmedchem.8b01558

subject

Has Abstract

pub_date

2019-02-14 00:00:00

pages

1407-1419

issue

3

eissn

0022-2623

issn

1520-4804

journal_volume

62

pub_type

杂志文章

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