A5022146690- Pancreatic function and diabetes
- Carbohydrate Chemistry and Synthesis
- Diabetes Treatment and Management
- Cardiac Ischemia and Reperfusion
- Glycosylation and Glycoproteins Research
- Ion channel regulation and function
- Diabetes Management and Research
- Diet, Metabolism, and Disease
- Epigenetics and DNA Methylation
- Fibroblast Growth Factor Research
- Cannabis and Cannabinoid Research
- Chemical Reaction Mechanisms
- Marine Sponges and Natural Products
- Neuroscience and Neuropharmacology Research
- Structural and Chemical Analysis of Organic and Inorganic Compounds
- X-ray Diffraction in Crystallography
- Synthesis of Organic Compounds
- Microbial Natural Products and Biosynthesis
- Pharmacogenetics and Drug Metabolism
- Synthesis and Biological Evaluation
- Biochemical and Molecular Research
- Phenothiazines and Benzothiazines Synthesis and Activities
- Pharmacological Receptor Mechanisms and Effects
- Cardiac electrophysiology and arrhythmias
- Monoclonal and Polyclonal Antibodies Research
Novo Nordisk (Denmark)
2001-2024
Université Libre de Bruxelles
2004
Technical University of Denmark
1997
Aarhus University
1997
Here, we describe the molecular engineering of insulin icodec to achieve a plasma half-life 196 h in humans, suitable for once-weekly subcutaneously administration. Insulin is based on re-engineering ultra-long oral basal OI338 with 70 humans. This systematic was accomplished by (1) further increasing albumin binding changing fatty diacid from 1,18-octadecanedioic acid (C18) 1,20-icosanedioic (C20) and (2) reducing receptor affinity B16Tyr → His substitution. selected screening long...
Mibefradil is a Ca<sup>2+</sup> channel antagonist that inhibits both T-type and high-voltage-activated channels. We previously showed block of channels by mibefradil occurs through the production an active metabolite intracellular hydrolysis. In present study, we modified structure to develop nonhydrolyzable analog, (1<i>S</i>, 2<i>S</i>)-2-(2-(<i>N</i>-[(3-benzimidazol-2-yl)propyl]-<i>N</i>-methylamino)ethyl)-6-fluoro-1,2,3,4-tetrahydro-1-isopropyl-2-naphtyl cyclopropanecarboxylate...
Recently, the first basal oral insulin (OI338) was shown to provide similar treatment outcomes glargine in a phase 2a clinical trial. Here, we report engineering of novel class analogues which OI338, 10, this publication, successfully tested We found that introduction two substitutions, A14E and B25H, needed increased stability toward proteolysis. Ultralong pharmacokinetic profiles were obtained by attaching an albumin-binding side chain derived from octadecanedioic (C18) or icosanedioic...
6-Chloro-3-alkylamino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide derivatives were synthesized and characterized as activators of adenosine 5'-triphosphate (ATP) sensitive potassium (K(ATP)) channels in the beta-cells by measuring effects on membrane potential insulin release vitro. The vascular tissue vitro measured rat aorta small mesenteric vessels. Selected compounds competitive inhibitors [(3)H]glibenclamide binding to membranes HEK293 cells expressing human SUR1/Kir6.2 potent...
Fibroblast growth factors (FGF) 19, 21 and 23 are characterized by being endocrinely secreted require co-receptor α-klotho or β-klotho (BKL) for binding activation of the FGF receptors (FGFR). FGF15 is rodent orthologue human FGF19, but two proteins share only 52% amino acid identity. Despite physiological role FGF21 FGF19 quite different, both lower blood glucose (BG) when administered to diabetic mice. The present study was designed clarify why with distinct functions BG in db/db mice if...
Here, we describe the development of FGF21 analog zalfermin (NNC0194-0499, 15), intended for once-weekly sc dosing. Protein engineering was needed to address inherent druggability issues natural hormone. Thus, deamidation Asp121 solved by mutation glutamine, and oxidation Met168 leucine. N-terminal region degradation dipeptidyl peptidase IV prevented alanine residue elongation. To prevent inactivating metabolism fibroblast activation protein carboxypeptidase-like activity in C-terminal...
Abstract A 2‐deoxyisomaltose analogue of acarbose was stereoselectively synthesised in 11 steps with a total yield 7% starting from 2,6‐dibromo‐2, 6‐dideoxy‐D‐mannono‐1,4‐lactone ( 6 ). The latter reduced to the lactol, converted methyl glycoside 7 ) and hydrogenated 6‐bromo‐2,6‐dideoxyglycoside 8 Benzylation hydroxy groups, elimination bromine 5‐ene Ferrier carbocyclisation gave (2 S , 3 R )‐2,3‐bisbenzyloxycyclohex‐5‐enone 12 1, 2‐addition benzyloxymethyl lithium at –110°C 6:1 mixture...
A. Hansen, T. M. Tagmose and Bols, Chem. Commun., 1996, 2649 DOI: 10.1039/CC9960002649
Phenylcyanoguanidines substituted with lipophilic electron-withdrawing functional groups, e.g. N-cyano-N'-[3,5-bis-(trifluoromethyl)phenyl]-N' '-(cyclopentyl)guanidine (10) and N-cyano-N'-(3,5-dichlorophenyl)-N' '-(3-methylbutyl)guanidine (12) were synthesized investigated for their ability to inhibit insulin release from beta cells, repolarize cell membrane potential, relax precontracted rat aorta rings. Structural modifications gave compounds, which selectively betaTC6 cells (e.g. compound...
Here, we describe molecular engineering of monovalent ultra-long acting two-chain insulin-Fc conjugates. Insulin-Fc conjugates were synthesized using trifunctional linkers with one amino reactive group for reaction a lysine residue insulin and two thiol groups used re-bridging disulfide bond within the Fc molecule. The pharmacokinetic profile was result concertedly slowing receptor-mediated clearance by (1) introduction acid substitutions that lowered receptor affinity (2) conjugating to...
Pharmacokinetic properties of a peptide hormone are extended via the combination fatty acid acylation and Fc-conjugation, as shown with double protracted insulin analogs. This approach may be expanded to other peptide- protein-based therapies.
Abstract ChemInform is a weekly Abstracting Service, delivering concise information at glance that was extracted from about 100 leading journals. To access of an article which published elsewhere, please select “Full Text” option. The original trackable via the “References”
Abstract ChemInform is a weekly Abstracting Service, delivering concise information at glance that was extracted from about 100 leading journals. To access of an article which published elsewhere, please select “Full Text” option. The original trackable via the “References”
Abstract ChemInform is a weekly Abstracting Service, delivering concise information at glance that was extracted from about 100 leading journals. To access of an article which published elsewhere, please select “Full Text” option. The original trackable via the “References”
Abstract ChemInform is a weekly Abstracting Service, delivering concise information at glance that was extracted from about 100 leading journals. To access of an article which published elsewhere, please select “Full Text” option. The original trackable via the “References”