ABSTRACT
A scaffold hopping strategy was successfully applied in discovering 2-aminooxazole amides as potent DGAT1 inhibitors for the treatment of dyslipidemia. Further optimization in potency and PK properties resulted in a lead series with oral in vivo efficacy in a mouse postprandial triglyceridemia (PPTG) assay.
Subject(s)
Amides/pharmacology , Diacylglycerol O-Acyltransferase/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Oxazoles/pharmacology , Triglycerides/blood , Animals , Humans , Mice , Molecular Structure , Structure-Activity RelationshipABSTRACT
Biaryl urea lead compound 1 was discovered earlier in our MCH antagonist program. Novel benzimidazole analogues with increased chemical stability, devoid of the potential carcinogenic liability associated with a biarylamine moiety, were synthesized and evaluated to be potent MCH R1 antagonists. Two compounds in this series have demonstrated in vivo efficacy in a rodent obesity model.
Subject(s)
Anti-Obesity Agents/chemical synthesis , Anti-Obesity Agents/pharmacology , Benzimidazoles/chemical synthesis , Benzimidazoles/pharmacology , Body Weight/drug effects , Receptors, Pituitary Hormone/antagonists & inhibitors , Administration, Oral , Animals , Disease Models, Animal , Drug Design , Rats , Structure-Activity RelationshipABSTRACT
A series of aminoalkylazetidines has been discovered as novel ORL1 receptor ligands. Structure-activity relationships have been investigated at the azetidine N and the alkyl side chain sites. Several potent and selective analogues have been identified.
Subject(s)
Azetidines/chemical synthesis , Azetidines/pharmacology , Receptors, Opioid/drug effects , Animals , Binding, Competitive/drug effects , CHO Cells , Cricetinae , Diprenorphine/pharmacology , Guanosine 5'-O-(3-Thiotriphosphate)/metabolism , Humans , Indicators and Reagents , Ligands , Narcotic Antagonists/pharmacology , Opioid Peptides/metabolism , Stereoisomerism , Structure-Activity Relationship , Nociceptin Receptor , NociceptinABSTRACT
The molecular mechanisms of cholesterol absorption in the intestine are poorly understood. With the goal of defining candidate genes involved in these processes a fluorescence-activated cell sorter-based, retroviral-mediated expression cloning strategy has been devised. SCH354909, a fluorescent derivative of ezetimibe, a compound which blocks intestinal cholesterol absorption but whose mechanism of action is unknown, was synthesized and shown to block intestinal cholesterol absorption in rats. Pools of cDNAs prepared from rat intestinal cells enriched in enterocytes were introduced into BW5147 cells and screened for SCH354909 binding. Several independent clones were isolated and all found to encode the scavenger receptor class B, type I (SR-BI), a protein suggested by others to play a role in cholesterol absorption. SCH354909 bound to Chinese hamster ovary (CHO) cells expressing SR-BI in specific and saturable fashion and with high affinity (K(d) approximately 18 nM). Overexpression of SR-BI in CHO cells resulted in increased cholesterol uptake that was blocked by micromolar concentrations of ezetimibe. Analysis of rat intestinal sections by in situ hybridization demonstrated that SR-BI expression was restricted to enterocytes. Cholesterol absorption was determined in SR-B1 knockout mice using both an acute, 2-h, assay and a more chronic fecal dual isotope ratio method. The level of intestinal cholesterol uptake and absorption was similar to that seen in wild-type mice. When assayed in the SR-B1 knockout mice, the dose of ezetimibe required to inhibit hepatic cholesterol accumulation induced by a cholesterol-containing 'western' diet was similar to wild-type mice. Thus, the binding of ezetimibe to cells expressing SR-B1 and the functional blockade of SR-B1-mediated cholesterol absorption in vitro suggest that SR-B1 plays a role in intestinal cholesterol metabolism and the inhibitory activity of ezetimibe. In contrast studies with SR-B1 knockout mice suggest that SR-B1 is not essential for intestinal cholesterol absorption or the activity of ezetimibe.
Subject(s)
CD36 Antigens/metabolism , Cholesterol/metabolism , Intestinal Mucosa/metabolism , Membrane Proteins , Receptors, Immunologic , Receptors, Lipoprotein , Animals , Anticholesteremic Agents/pharmacology , Azetidines/pharmacology , CD36 Antigens/biosynthesis , CD36 Antigens/genetics , CHO Cells , Cholesterol/blood , Cloning, Molecular , Cricetinae , Dose-Response Relationship, Drug , Ezetimibe , Flow Cytometry , Gene Library , In Situ Hybridization , Intestinal Absorption/drug effects , Liver/drug effects , Liver/metabolism , Male , Mice , Mice, Knockout , Microscopy, Fluorescence , RNA, Messenger/metabolism , Rats , Rats, Sprague-Dawley , Receptors, Scavenger , Scavenger Receptors, Class BABSTRACT
The discoveries of Sch 48461 and Sch 58235 and their novel pharmacology of inhibition of cholesterol absorption have prompted efforts to determine their biological mechanism of action (MOA). To this end, a series of radioiodinated analogues with good to excellent in vivo activity have been designed and synthesized as single enantiomers. They are structurally consistent with the allowable SAR of the 2-azetidinone class of cholesterol absorption inhibitors.
Subject(s)
Anticholesteremic Agents/chemical synthesis , Anticholesteremic Agents/pharmacology , Azetidines/chemical synthesis , Azetidines/pharmacology , Cholesterol/pharmacokinetics , Intestinal Absorption/drug effects , Animals , Azetidines/chemistry , Cricetinae , Drug Design , Ezetimibe , Isotope Labeling , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Fluorescent analogues of the cholesterol absorption inhibitor (CAI), Sch 58235, have been designed and synthesized as single enantiomers. Biological testing reveals that they are potent CAIs and are suitable tools for the investigation of the azetidinone CAI mechanism of action (MOA).
