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Dual Agonists (dual + agonist)

Distribution by Scientific Domains
Chemistry75%

Selected Abstracts

ChemInform Abstract: Design and Synthesis of Novel and Potent Amide Linked PPAR,/, Dual Agonists.

CHEMINFORM, Issue 11 2008
Qing Shi
Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a "Full Text" option. The original article is trackable via the "References" option. [source]

The First Potent Subtype-Selective Retinoid X Receptor (RXR) Agonist Possessing a 3-Isopropoxy-4-isopropylphenylamino Moiety, NEt-3IP (RXR,/,-dual agonist)

CHEMMEDCHEM, Issue 5 2008
Kayo Takamatsu
Abstract Retinoid X receptor (RXR) agonists (rexinoids) are attracting much attention for their use in treatment of cancers, including tamoxifen-resistant breast cancer and taxol-resistant lung cancer, and metabolic disease. However, known RXR agonists have a highly lipophilic character. In addition, no subtype-selective RXR agonists have been found. We previously reported an RXR,-preferential agonist 4-[N -methanesulfonyl- N -(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)amino]benzoic acid (6,a). The RXR agonistic activity is much less than that of well-known RXR agonists. To develop potent, less-lipophilic, and subtype-selective RXR agonists, we created new RXR agonists possessing alkoxy and isopropyl groups as a lipophilic domain of the common structure of well-known RXR agonists. As a result, compounds possessing branched alkoxy groups, 6-[N -ethyl- N -(3-isopropoxy-4-isopropylphenyl)amino]nicotinic acid (NEt-3IP: 7,a) and 6-[N -ethyl- N -(3-isobutoxy-4-isopropylphenyl)amino]nicotinic acid (NEt-3IB: 7,c), showed RXR agonistic activity as potent as, or more potent than, the activities of representative RXR agonists. Moreover, NEt-3IP (7,a) was found to be the first RXR,/,-selective (or RXR,/,-dual) agonist. Being potent, less lipophilic, and having RXR subtype-selective activity, NEt-3IP (7,a) is expected to become a new drug candidate and to be a useful biological tool for clarifying each RXR subtype function. [source]

Preferential localization of recombinant factor VIIa to platelets activated with a combination of thrombin and a glycoprotein VI receptor agonist

JOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 4 2007
M. KJALKE
Summary., Background:, Activation of platelets with a combination of collagen and thrombin generates a subpopulation of highly procoagulant ,coated' platelets characterized by high surface expression of fibrinogen and other procoagulant proteins. Objectives:, To analyze the interaction of recombinant factor VIIa (rFVIIa) with coated platelets. Methods and results:, rFVIIa localized to the coated platelets in flow cytometry experiments, while minimal rFVIIa was found on platelets activated with adenosine diphosphate, thrombin or via glycoprotein VI individually, and essentially no rFVIIa was found on non-stimulated platelets. Removal of the , -carboxyglutamic acid (Gla) domain of rFVIIa, and addition of EDTA, annexin V or excess prothrombin inhibited rFVIIa localization to the coated platelets, indicating that the interaction was mediated by the calcium-dependent conformation of the Gla domain and platelet exposure of negatively charged phospholipids. A reduced level of platelet fibrinogen exposure was observed at hemophilia A-like conditions in a model system of cell-based coagulation, indicating that coated platelet formation in hemophilia may be diminished. Addition of rFVIIa dose-dependently enhanced thrombin generation and partly restored platelet fibrinogen exposure. Conclusions:, The data suggest that rFVIIa localized preferentially on platelets activated with dual agonists, thereby ensuring enhanced thrombin generation localized at the site of injury where both collagen and tissue factor are exposed, the latter ensuring the formation of thrombin necessary for coated platelet formation. [source]

Novel Pirinixic Acids as PPAR, Preferential Dual PPAR,/, Agonists

MOLECULAR INFORMATICS, Issue 5 2009
Heiko Zettl
Abstract Pirinixic acid is a moderate agonist of both the alpha and the gamma subtype of the peroxisome proliferator activated receptor (PPAR). Previously, we have shown that ,-alkyl substitution leads to balanced low micromolar-active dual agonists of PPAR, and PPAR,. Taking ,-hexyl pirinixic acid as a new scaffold, we further optimized PPAR activity by enlargement of the lipophilic backbone by substituting the 2,3-dimethylphenyl with biphenylic moieties. Such a substitution pattern had only minor impact on PPAR, activity but further increased PPAR, activity leading to nanomolar activities. Supporting docking studies proposed that the (R)-enantiomer should fit the PPAR, ligand-binding pocket better and thus be more active than the (S)-enantiomer. Single enantiomers of selected active analogues were then prepared by enantio-selective synthesis and enantio-selective preparative HPLC, respectively. Biological data for the distinct enantiomers fully corroborated the docking experiments and substantiate a stereochemical impact on PPAR activation. [source]