Preparation and Pharmaceutical Characterizations of Lipidated Dimeric Xenopus Glucagon-Like Peptide-1 Conjugates
A pair of glucagon-like peptide-1 (GLP-1) analogs (1 and 2) were synthesized by hybridizing the key sequences of GLP-1, exendin-4, lixisenatide, and xenGLP-1B (Xenopus GLP-1 analog). To achieve long-acting hypoglycemic effects and to further improve their anti-diabetic potencies, lipidization and dimerization strategies were used to afford two lipidated dimeric conjugates (9 and 11). Conjugates 9 and 11 showed stronger receptor activation potency than GLP-1 and exendin-4 in vitro. Moreover, 9 and 11 exhibited superior hypoglycemic and insulinotropic activities to liraglutide in type 2 diabetic C57BL/6J-m+/+ Leprdb (db/db) mice. Pharmacokinetic studies revealed that the circulating half-lives (t1/2) of 9 and 11 were 2.3- and 1.7-fold longer than that of liraglutide. The improved pharmacokinetic profiles led to significantly protracted in vivo anti-diabetic effects as confirmed by multiple oral glucose tolerance tests and hypoglycemic duration tests. Most importantly, chronic treatment studies found that on...
We recently generalized the formerly alignment-dependent multivariate image analysis applied to quantitative structure–activity relationships (MIA-QSAR) method through the application of the discrete Fourier transform (DFT), allowing for its application to noncongruent and structurally dive ... more
Poly-ADP-ribosylation (PARylation) is a protein posttranslational modification (PTM) that is critically involved in many biological processes that are linked to cell stress responses. It is catalyzed by a class of enzymes known as poly-ADP-ribose polymerases (PARPs). In particular, PARP1 is ... more
This review focuses on the type A cytochrome c oxidases (CcO), which are found in all mitochondria and also in several aerobic bacteria. CcO catalyzes the respiratory reduction of dioxygen (O2) to water by an intriguing mechanism, the details of which are fairly well understood today as a r ... more
Rohm and Haas Powder Coatings is delighted to announce that its Reading, Pennsylvania, facility is the first site in the world to receive the RCMS® Site Certification awarded by the American Chemical Council (ACC).
When Raj Gupta, Chairman and CEO of Rohm and Haas Company, became Chairman ... more