RESUMO
A collective synthesis of 8,14-dihydronorsalutaridine, 8,14-dihydrosalutaridine, norisosinomenine, and isosinomenine is reported. The strategy provides direct access to the correct oxidation level of the products. The combination of an organocatalyst guanidine superbase, a tertiary amine base, and a dehydrating agent was necessary for the successful Henry-Michael-dehydration cascade to form the phenanthrene motif. The required selective aliphatic nitro reduction could only be achieved under heterogeneous transfer-hydrogenation conditions.
Assuntos
Alcaloides/síntese química , Morfinanos/síntese química , Alcaloides/química , Aminas/química , Hidrogenação , Estrutura Molecular , Morfinanos/química , Oxirredução , EstereoisomerismoRESUMO
(-)-Codeine 1 was converted into previously unknown 7ß-methyl-7,8-dihydrocodeine/morphine derivatives such as 13 via classical diaxial opening of α-epoxide 3. Several analogs exhibited dual µ/δ-agonist activity.
Assuntos
Codeína/análogos & derivados , Codeína/farmacologia , Receptores Opioides delta/agonistas , Receptores Opioides mu/agonistas , Animais , Compostos de Epóxi/química , Compostos de Epóxi/farmacologia , Humanos , Camundongos , Modelos Moleculares , Morfinanos/química , Morfinanos/farmacologia , Receptores Opioides delta/metabolismo , Receptores Opioides mu/metabolismoRESUMO
A new P1' group for TACE inhibitors was identified by eliminating the oxygen atom in the linker of the original 4-(2-methylquinolin-4-ylmethoxy)phenyl P1' group. Incorporation of this 4-(2-methylquinolin-4-ylmethyl)phenyl group onto different beta-aminohydroxamic acid cores provided compound 18, which demonstrated potent porcine TACE (p-TACE) and human whole blood activity, excellent PK properties, and good selectivity against a variety of MMPs.
Assuntos
Proteínas ADAM/antagonistas & inibidores , Química Farmacêutica/métodos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/síntese química , Ácidos Hidroxâmicos/química , Proteínas ADAM/sangue , Proteína ADAM17 , Animais , Cães , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Humanos , Concentração Inibidora 50 , Modelos Químicos , Conformação Molecular , Oxigênio/química , Ratos , Relação Estrutura-Atividade , SuínosRESUMO
Replacement of the amide functionality in IM491 (N-hydroxy-(5S,6S)-1-methyl-6-[[4-(2-methyl-4-quinolinylmethoxy)anilinyl]carbonyl]5-piperidinecarboxamide) with a sulfonyl group led to a new series of alpha,beta-cyclic and beta,beta-cyclic gamma-sulfonyl hydroxamic acids, which were potent TNF-alpha converting enzyme (TACE) inhibitors. Among them, inhibitor 4b (N-hydroxy-(4S,5S)-1-methyl-5-[[4-(2-methyl-4-quinolinylmethoxy)phenyl]sulfonylmethyl]-4-pyrrolidinecarboxamide) exhibited IC50 values of < 1 nM and 180 nM in porcine TACE (pTACE) and cell assays, respectively, with excellent selectivity over MMP-1, -2, -9 and -13 and was orally bioavailable with an F value of 46% in mice.
Assuntos
Metaloendopeptidases/antagonistas & inibidores , Inibidores de Proteases/síntese química , Sulfonas/síntese química , Fator de Necrose Tumoral alfa/metabolismo , Proteínas ADAM , Proteína ADAM17 , Animais , Células CACO-2 , Humanos , Metaloendopeptidases/metabolismo , Camundongos , Inibidores de Proteases/farmacologia , Ratos , Relação Estrutura-Atividade , Sulfonas/farmacologiaRESUMO
A series of peptide boronic acids containing extended, hydrophobic P1 residues was prepared to probe the shallow, hydrophobic S1 region of HCV NS3 protease. The p-trifluoromethylphenethyl P1 substituent was identified as optimal with respect to inhibitor potency for NS3 and selectivity against elastase and chymotrypsin.
