RESUMO
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.
Assuntos
Oxazóis/síntese química , Piridonas/síntese química , Receptores de Prostaglandina E Subtipo EP3/antagonistas & inibidores , Administração Oral , Animais , Disponibilidade Biológica , Humanos , Estrutura Molecular , Oxazóis/química , Oxazóis/farmacologia , Ligação Proteica/efeitos dos fármacos , Piridonas/química , Piridonas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de Prostaglandina E Subtipo EP3/química , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Aminoquinolinas/síntese química , Aminoquinolinas/farmacologia , Inibidores da Agregação Plaquetária/síntese química , Inibidores da Agregação Plaquetária/farmacologia , Antagonistas do Receptor Purinérgico P2 , Aminoquinolinas/química , Técnicas de Química Combinatória , Humanos , Estrutura Molecular , Inibidores da Agregação Plaquetária/química , Receptores Purinérgicos P2/metabolismo , Receptores Purinérgicos P2Y1 , Estereoisomerismo , Relação Estrutura-Atividade , Trombose/tratamento farmacológicoRESUMO
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.
Assuntos
Ácidos/química , Compostos Alílicos/química , Compostos de Trimetilsilil/química , CatáliseRESUMO
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.
Assuntos
Depsipeptídeos/química , Oligopeptídeos/síntese química , Peptídeos Cíclicos/química , Espectroscopia de Ressonância Magnética , Metilação , Estrutura Molecular , Oligopeptídeos/químicaRESUMO
[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.
Assuntos
Aminoácidos/química , Depsipeptídeos/síntese química , Guanidinas/química , Ácidos Heptanoicos/química , Animais , Estrutura Molecular , Poríferos/químicaRESUMO
[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.