ABSTRACT
Multiple regions of the 3-oxazolidinedione-6-naphthyl-pyridinone series identified via high throughput screening were explored. SAR studies of these regions including the left-hand side oxazolidinedione moiety, α-substituent on the oxazolidinedione ring, central pyridinone core, and substituents on the central pyridinone core led to the discovery of potent EP(3) receptor antagonists such as compound 29 which possesses outstanding rat pharmacokinetic properties. Synthesis and SAR of these novel compounds and DMPK properties of representative compounds are discussed.
Subject(s)
Oxazoles/chemical synthesis , Pyridones/chemical synthesis , Receptors, Prostaglandin E, EP3 Subtype/antagonists & inhibitors , Administration, Oral , Animals , Biological Availability , Humans , Molecular Structure , Oxazoles/chemistry , Oxazoles/pharmacology , Protein Binding/drug effects , Pyridones/chemistry , Pyridones/pharmacology , Rats , Rats, Sprague-Dawley , Receptors, Prostaglandin E, EP3 Subtype/chemistry , Structure-Activity RelationshipABSTRACT
High-throughput screening of the GSK compound collection against the P2Y(1) receptor identified a novel series of tetrahydro-4-quinolinamine antagonists. Optimal substitution around the piperidine group was pivotal for ensuring activity. An exemplar analog from this series was shown to inhibit platelet aggregation.
Subject(s)
Aminoquinolines/chemical synthesis , Aminoquinolines/pharmacology , Platelet Aggregation Inhibitors/chemical synthesis , Platelet Aggregation Inhibitors/pharmacology , Purinergic P2 Receptor Antagonists , Aminoquinolines/chemistry , Combinatorial Chemistry Techniques , Humans , Molecular Structure , Platelet Aggregation Inhibitors/chemistry , Receptors, Purinergic P2/metabolism , Receptors, Purinergic P2Y1 , Stereoisomerism , Structure-Activity Relationship , Thrombosis/drug therapyABSTRACT
Allylation reagents, which possess geminal bis-trimethylsilyl substitution, are readily prepared from E- or Z-alkenyl bromides. The reactivity of 3,3-bis(trimethylsilyl)-2-methyl-1-propene (1) is described and predominantly provides ene reactions with aldehydes to give alcohol 2 in the presence of BF3.OEt2. Alternatively, Sakurai allylation reactions of 1 are observed by using stronger Lewis acids in methylene chloride to exclusively yield E-trisubstituted alkenylsilanes 3.
Subject(s)
Acids/chemistry , Allyl Compounds/chemistry , Trimethylsilyl Compounds/chemistry , CatalysisABSTRACT
Two possible isomers of the natural product callipeltin E (1, 5) were synthesized by using an Fmoc-based solid-phase strategy in 7 steps, in 20% and 26% overall yields, respectively. The (1)H NMR spectrum of synthetic 5 correlated closely with that of the natural product, whereas that of 1 did not, providing confirmation of the configurational reassignment of the N-terminal residue of callipeltin E as D-allothreonine. This result strongly implies that the corresponding residue in the closely related cyclic depsipeptides callipeltins A and B should also be considered a D-allothreonine residue.
Subject(s)
Depsipeptides/chemistry , Oligopeptides/chemical synthesis , Peptides, Cyclic/chemistry , Magnetic Resonance Spectroscopy , Methylation , Molecular Structure , Oligopeptides/chemistryABSTRACT
[structure: see text] The lipopeptide callipeltin D (1) was synthesized using an Fmoc-based solid-phase strategy in seven steps and 35% overall yield. The 1H NMR of synthetic 1 correlated closely with that of the natural product, confirming the configurational assignment of the novel amino acid constituent (2R,3R,4S)-4-amino-7-guanidino-2,3-dihydroxyheptanoic acid.
Subject(s)
Amino Acids/chemistry , Depsipeptides/chemical synthesis , Guanidines/chemistry , Heptanoic Acids/chemistry , Animals , Molecular Structure , Porifera/chemistryABSTRACT
[reaction: see text] The novel amino acid residue (2R,3R,4S)-4-amido-7-guanidino-2,3-dihydroxyheptanoic acid (AGDHE, 3), a constituent of the cyclic depsipeptides callipeltins A and D, and its (2S,3S,4S) diastereomer were synthesized from a protected L-ornithine derivative in 13 steps (15% overall yield), and its configurational assignment was reexamined by (1)H NMR.
