ABSTRACT
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.
Subject(s)
Alkaloids/chemical synthesis , Morphinans/chemical synthesis , Alkaloids/chemistry , Amines/chemistry , Hydrogenation , Molecular Structure , Morphinans/chemistry , Oxidation-Reduction , StereoisomerismABSTRACT
(-)-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.
Subject(s)
Codeine/analogs & derivatives , Codeine/pharmacology , Receptors, Opioid, delta/agonists , Receptors, Opioid, mu/agonists , Animals , Epoxy Compounds/chemistry , Epoxy Compounds/pharmacology , Humans , Mice , Models, Molecular , Morphinans/chemistry , Morphinans/pharmacology , Receptors, Opioid, delta/metabolism , Receptors, Opioid, mu/metabolismABSTRACT
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.
Subject(s)
ADAM Proteins/antagonists & inhibitors , Chemistry, Pharmaceutical/methods , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/chemical synthesis , Hydroxamic Acids/chemistry , ADAM Proteins/blood , ADAM17 Protein , Animals , Dogs , Drug Design , Enzyme Inhibitors/pharmacology , Humans , Inhibitory Concentration 50 , Models, Chemical , Molecular Conformation , Oxygen/chemistry , Rats , Structure-Activity Relationship , SwineABSTRACT
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.
Subject(s)
Metalloendopeptidases/antagonists & inhibitors , Protease Inhibitors/chemical synthesis , Sulfones/chemical synthesis , Tumor Necrosis Factor-alpha/metabolism , ADAM Proteins , ADAM17 Protein , Animals , Caco-2 Cells , Humans , Metalloendopeptidases/metabolism , Mice , Protease Inhibitors/pharmacology , Rats , Structure-Activity Relationship , Sulfones/pharmacologyABSTRACT
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.
