ABSTRACT
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
Modifications of the lead TACE inhibitor 1 (N-hydroxy-trans-2-[[4-(4-quinolinyloxymethyl)anilinyl]carbonyl]-1-cyclohexanecarboxamide) at the cyclohexyl ring and the quinoline moiety led to the identification of a series of piperidine containing TACE inhibitors with potent activity in the inhibition of TNF-alpha release in the whole blood assay (WBA). The most potent analogue IM491 [N-hydroxy-(5S,6S)-1-methyl-6-[[4-(2-methyl-4-quinolinylmethoxy)anilinyl]carbonyl]-5-piperidinecarboxamide] exhibited an IC(50) value of 20 nM in WBA with excellent selectivity over MMP-1, -2 and -9 and is orally bioavailable with an F value of 43% in beagle dogs.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Metalloendopeptidases/antagonists & inhibitors , Succinates/chemical synthesis , ADAM Proteins , ADAM17 Protein , Drug Design , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Kinetics , Models, Molecular , Molecular Conformation , Structure-Activity Relationship , Succinates/chemistry , Succinates/pharmacologyABSTRACT
Rational design based on the broad spectrum MMP inhibitor CGS 27023A led to the identification of a novel series of cyclic succinate TACE inhibitors. As a mixture of two enantiomers, the lead compound 17b exhibited potent enzyme activity (IC(50)=8 nM) in the inhibition of porcine TNF-alpha converting enzyme (pTACE) and excellent selectivity over aggrecanase and MMP-1, -2 and -9.
Subject(s)
Enzyme Inhibitors/pharmacology , Metalloendopeptidases/antagonists & inhibitors , Succinates/pharmacology , ADAM Proteins , ADAM17 Protein , Drug Design , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Hydroxamic Acids/pharmacology , Models, Molecular , Molecular Conformation , Protease Inhibitors/pharmacology , Pyrazines/pharmacology , Structure-Activity Relationship , Succinates/chemical synthesis , Succinates/chemistry , Sulfonamides/pharmacologyABSTRACT
Asymmetric syntheses of (2S,3S)-3-(tert-butoxycarbonyl)-2-piperidinecarboxylic acid (1b), (3R,4S)-4-(tert-butoxycarbonyl)-3-piperidinecarboxylic acid (2b), and their corresponding N-Boc and N-Cbz protected analogues 8a,b and 17a,b are described. Enantiomerically pure 1b has been synthesized in five steps starting from L-aspartic acid beta-tert-butyl ester. Tribenzylation of the starting material followed by alkylation with allyl iodide using KHMDS produces the key intermediate 5a in a 6:1 diastereomeric excess. Upon hydroboration, the alcohol 6a is oxidized, and the resulting aldehyde 7 is subjected to a ring closure via reductive amination, providing 1b in an overall yield of 38%. Optically pure 2b has been synthesized beginning with N-Cbz-beta-alanine. The synthesis involves the induction of the first stereogenic center using Evans's chemistry and sequential LDA-promoted alkylations with tert-butyl bromoacetate and allyl iodide. Further elaboration by ozonolysis and reductive amination affords 2b in an overall yield of 28%.
