ABSTRACT
Scaffold hopping from the amide group of lead compound ONO-7300243 (1) to a secondary alcohol successfully gave a novel chemotype lysophosphatidic acid receptor 1 (LPA1) antagonist 4. Wash-out experiments using rat isolated urethra showed that compound 4 possesses a tight binding feature to the LPA1 receptor. Further modification of two phenyl groups of 1 to pyrrole and an indane moiety afforded an optimized compound ONO-0300302 (19). Despite its high i.v. clearance, 19 inhibited significantly an LPA-induced increase of intraurethral pressure (IUP) in rat (3 mg/kg, p.o.) and dog (1 mg/kg, p.o.) over 12 h. Binding experiments with [3H]-ONO-0300302 suggest that the observed long duration action is because of the slow tight binding character of 19.
ABSTRACT
A series of 4-(4-phenoxy)benzoylamino-4-methoxymethyloxymethyl butyric acid hydroxamates, which were derived from l-glutamic acid, were synthesized and evaluated as matrix metalloproteinase inhibitors. Most of the compounds listed in exhibited strong inhibitory activity against MMP-2 and MMP-9, as well as even stronger inhibitory activity against MMP-3, but showed relatively weak inhibition of MMP-1. Structure-activity relationships are discussed.
Subject(s)
Benzamides , Drug Design , Hydroxamic Acids , Matrix Metalloproteinase Inhibitors , Protease Inhibitors , Administration, Oral , Animals , Benzamides/chemical synthesis , Benzamides/chemistry , Benzamides/pharmacology , Drug Evaluation, Preclinical , Enzyme Activation/drug effects , Glutamic Acid/chemistry , Guinea Pigs , Hydroxamic Acids/chemical synthesis , Hydroxamic Acids/chemistry , Hydroxamic Acids/pharmacology , Male , Molecular Conformation , Protease Inhibitors/administration & dosage , Protease Inhibitors/chemical synthesis , Protease Inhibitors/chemistry , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A series of N-benzoyl 4-aminobutyric acid hydroxamate analogs were synthesized and evaluated as matrix metalloproteinase inhibitors. Synthetic work was focused on the chemical modification of the 4-aminobutyric acid part using easily available starting materials. As such, chemical modification was carried out using commercially available starting materials such as 4-aminobutyric acid, (+)- and (-)-malic acid, and D- and L-glutamic acid derivatives. Among the compounds tested, N-[4-(benzofuran-2-yl)benzoyl] 4-amino-4S-hydroxymethylbutyric acid hydroxamates derived from L-glutamic acid demonstrated more potent inhibitory activity against MMP-2 and MMP-9 compared with the corresponding 2S-hydroxy analogs or 3S-hydroxy analogs, respectively, which were derived from (-)-malic acid. Structure-activity relationship study is presented.
Subject(s)
Benzofurans , Butyrates , Drug Design , Enzyme Inhibitors/chemical synthesis , Matrix Metalloproteinase Inhibitors , Tissue Inhibitor of Metalloproteinases , Benzofurans/chemical synthesis , Benzofurans/chemistry , Benzofurans/pharmacology , Butyrates/chemical synthesis , Butyrates/chemistry , Butyrates/pharmacology , Drug Evaluation, Preclinical , Enzyme Inhibitors/chemistry , Humans , Molecular Structure , Stereoisomerism , Structure-Activity Relationship , Tissue Inhibitor of Metalloproteinases/chemical synthesis , Tissue Inhibitor of Metalloproteinases/chemistry , Tissue Inhibitor of Metalloproteinases/pharmacologyABSTRACT
A series of N-benzoyl gamma-aminobutyric hydroxamic acids were synthesized and evaluated as matrix metalloproteinase inhibitors. First, we focused on chemical modification of the N-benzoyl residue. Introduction of electron-rich para-substituents was effective to increase the inhibitory activity. Especially, some of the analogs with relatively more planar N-acyl residues, such as 10 and 11, demonstrated more potent activity. Second, chemical modification of the gamma-aminobutyric hydroxamic acid moiety was carried out to optimize the three-dimensional arrangement of the two pharmacophores (hydroxamic acid and N-acyl residues). Among the tested, the gamma-aminobutyric hydroxamic acid moiety was found to be the best spacer for connecting the above-mentioned two pharmacophores. Synthesis and structure-activity relationships are discussed.
Subject(s)
Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Matrix Metalloproteinase Inhibitors , Drug Design , Enzyme Inhibitors/chemical synthesis , Humans , Molecular Structure , Structure-Activity RelationshipABSTRACT
Generation of structurally new matrix metalloproteinase inhibitors was successfully carried out using an in silico technique. In order to identify the small fragment interacting with residues in the S1' pocket of MMP-1 through hydrogen bonds, we performed in silico screening using the LUDI program. As a result, acetyl-L-alanyl-(N-methyl)amide (Ac-L-Ala-NHMe) was selected to link with another fragment, hydroxamic acid that interacted with catalytic zinc. By this approach, the L-glutamic acid derivative 2b was discovered to be a new type of matrix metalloproteinase inhibitor. Further transformation to reduce its peptidic nature and improve activity yielded nonpeptidic lead compounds as inhibitors of MMP-1, -2, -3, and -9.
