ABSTRACT
A series of 4-(3-biaryl)quinolines with sulfone substituents on the terminal aryl ring (8) was prepared as potential LXR agonists. High affinity LXRbeta ligands with generally modest binding selectivity over LXRalpha and excellent agonist potency in LXR functional assays were identified. Many compounds had LXRbeta binding IC(50) values <10 nM while the most potent had EC(50) values <1.0 nM in an ABCA1 mRNA induction assay in J774 mouse cells with efficacy comparable to T0901317. Sulfone 8a was further evaluated in LDL (-/-) mice and shown to reduce atherosclerotic lesion progression.
Subject(s)
Orphan Nuclear Receptors/agonists , Quinolines/chemistry , Sulfones/chemistry , Animals , Atherosclerosis/drug therapy , Binding Sites , Cell Line , Computer Simulation , Humans , Lipoproteins, LDL/deficiency , Lipoproteins, LDL/genetics , Lipoproteins, LDL/metabolism , Liver X Receptors , Mice , Mice, Knockout , Microsomes/metabolism , Orphan Nuclear Receptors/metabolism , Rats , Structure-Activity Relationship , Sulfones/chemical synthesis , Sulfones/therapeutic useABSTRACT
A series of 4-(3-aryloxyaryl)quinolines with sulfone substituents on the terminal aryl ring (7) was prepared as LXR agonists. High affinity LXR ligands with excellent agonist potency and efficacy in functional assays of LXR activity were identified. In general, these sulfone agonists were equal to or superior to previously described alcohol and amide analogs in terms of affinity, functional potency, and microsomal stability. Many of the sulfones had LXRbeta binding IC(50) values <10nM while the most potent compounds in an ABCA1 mRNA induction assay in J774 mouse cells had EC(50) values <10nM and were as efficacious as T0901317.
Subject(s)
Orphan Nuclear Receptors/agonists , Quinolines/chemistry , Sulfones/chemistry , ATP Binding Cassette Transporter 1 , ATP-Binding Cassette Transporters/genetics , ATP-Binding Cassette Transporters/metabolism , Animals , Binding Sites , Cell Line , Computer Simulation , Humans , Hydrocarbons, Fluorinated/chemistry , Hydrocarbons, Fluorinated/pharmacology , Hydrogen Bonding , Liver X Receptors , Mice , Microsomes, Liver/metabolism , Orphan Nuclear Receptors/metabolism , Quinolines/chemical synthesis , Quinolines/pharmacology , Rats , Structure-Activity Relationship , Sulfonamides/chemistry , Sulfonamides/pharmacology , Sulfones/chemical synthesis , Sulfones/pharmacologyABSTRACT
An efficient and mild method to couple aryl bromides and activated non-allylic alcohols in a Heck reaction with tandem isomerization to selectively afford high yields of 1,5-diarylalkan-1-ones has been developed. Mechanistic insight was gained through NMR studies of products derived from deuterium-labeled intermediates.
Subject(s)
Benzyl Alcohols/chemistry , Bromides/chemistry , Palladium/chemistry , Catalysis , Magnetic Resonance Spectroscopy , Molecular Structure , StereoisomerismABSTRACT
During the last thirty years, concern over stereoselectivity of drug action has drawn a great deal of interest within the pharmaceutical field due to an improved understanding of the pharmacology and pharmacokinetics of enantiomers. Developing single enantiomers versus racemates or introducing a single enantiomer following the development of the racemic mixture appears to be the new trend. The intellectual property status of single enantiomers from racemates may be unclear. Drug discoverers and patent attorneys must examine the examples of the past to establish an appropriate pathway towards the development and intellectual property protection of chiral drugs. The review will focus on the patenting of an enantiomer in view of the prior art disclosure for the racemic mixture.
Subject(s)
Drug Industry/legislation & jurisprudence , Patents as Topic/legislation & jurisprudence , Pharmaceutical Preparations/chemistry , Drug Design , Intellectual Property , Pharmaceutical Preparations/chemical synthesis , Stereoisomerism , United StatesABSTRACT
The design, synthesis, and biological evaluation of the 2-phenyl-isoindole-1,3-diones will be discussed. Detailed modeling studies with X-ray support were used to understand the ligand binding orientation and observed selectivity.
Subject(s)
Estrogen Receptor beta/agonists , Indoles/chemistry , Phthalimides/chemistry , Crystallography, X-Ray , Estrogen Receptor beta/chemistry , Humans , Indoles/chemical synthesis , Ligands , Phthalimides/chemical synthesisABSTRACT
A new series of 3,3-disubstituted-5-aryloxindoles has been synthesized and evaluated for progesterone receptor antagonist (PR) activity in a T47D cell alkaline phosphatase assay and for their ability to bind PR in competition binding studies. In this communication, the synthesis and structure-activity relationships (SARs) of various 3,3-substituents are discussed where it is clear that small alkyl and spiroalkyl groups are required to achieve better PR antagonist activity.
