ABSTRACT
Matrix metalloproteinase-7 (MMP-7) has emerged as a protein playing important roles in both physiological and pathophysiological processes. Despite the growing interest in MMP-7 as a potential therapeutic target for diseases including cancer and fibrosis, potent and selective MMP-7 inhibitors have yet to be identified. Compound 1, previously reported by Edman and co-workers, binds to the S1' subsite of MMP-7, exhibiting moderate inhibitory activity and selectivity. To achieve both higher inhibitory activity and selectivity, we conceived hybridizing 1 with short peptides. The initially designed compound 6, which was a hybrid molecule between 1 and a tripeptide (Ala-Leu-Met) derived from an MMP-2-inhibitory peptide (APP-IP), showed enhanced MMP-7-inhibitory activity. Subsequent optimization of the peptide moiety led to the development of compound 18 with remarkable potency for MMP-7 and selectivity over other MMP subtypes.
Subject(s)
Matrix Metalloproteinase 2 , Matrix Metalloproteinase Inhibitors , Humans , Matrix Metalloproteinase 2/metabolism , Matrix Metalloproteinase 7 , Matrix Metalloproteinase Inhibitors/chemistry , Peptides/pharmacologyABSTRACT
Prolyl hydroxylase domain-containing protein (PHD) inhibitors are useful as orally administered agents for the treatment of renal anemia. Based on the common structures of known PHD inhibitors, we found novel PHD inhibitor 1 with a 2-[(4-hydroxy-6-oxo-2,3-dihydro-1H-pyridine-5-carbonyl)amino]acetic acid motif. The PHD2-inhibitory activity, lipophilicity (CLogP), and PK profiles (hepatocyte metabolism, protein binding, and/or elimination half-life) of this inhibitor were used as the evaluation index to optimize the structure and eventually discovered clinical candidate 42 as the suitable compound. Compound 42 was demonstrated to promote the production of erythropoietin (EPO) following oral administration in mice and rats. The predicted half-life of this compound in humans was 1.3-5.6â¯h, therefore, this drug may be expected to administer once daily with few adverse effects caused by excessive EPO production.
Subject(s)
Acetic Acid/pharmacology , Anemia/drug therapy , Drug Discovery , Hypoxia-Inducible Factor-Proline Dioxygenases/antagonists & inhibitors , Prolyl-Hydroxylase Inhibitors/pharmacology , Renal Insufficiency, Chronic/drug therapy , Acetic Acid/administration & dosage , Acetic Acid/chemistry , Administration, Oral , Anemia/metabolism , Animals , Dogs , Dose-Response Relationship, Drug , Humans , Hypoxia-Inducible Factor-Proline Dioxygenases/metabolism , Mice , Molecular Structure , Prolyl-Hydroxylase Inhibitors/administration & dosage , Prolyl-Hydroxylase Inhibitors/chemistry , Rats , Renal Insufficiency, Chronic/metabolism , Structure-Activity RelationshipABSTRACT
Novel (4-piperidinyl)-piperazine derivatives were synthesized and evaluated as ACC1/2 non-selective inhibitors. Optimization of the substituents on the nitrogen of the piperidine ring led to the identification of the fluorine substituted tert-butoxycarbonyl group. Advanced analog, 1,1,1-trifluoro-2-methylpropan-2-yl 4-{4-[(2-amino-6-methyl-1-benzothiophen-3-yl)carbonyl]piperazin-1-yl}piperidine-1-carboxylate (12c) showed potent inhibitory activities in enzyme-assay and cell-based assays. Compound 12c also exhibited reduction of hepatic de novo fatty acid synthesis in rats after oral administration.
Subject(s)
Acetyl-CoA Carboxylase/antagonists & inhibitors , Fluorine/chemistry , Formic Acid Esters/chemistry , Piperazines/chemical synthesis , Piperidines/chemical synthesis , Acetyl-CoA Carboxylase/classification , Administration, Oral , Animals , Molecular Structure , Piperazine , Piperazines/chemistry , Piperazines/pharmacology , Piperidines/chemistry , Piperidines/pharmacology , Rats , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Acetyl-CoA carboxylases (ACCs), the rate limiting enzymes in de novo lipid synthesis, play important roles in modulating energy metabolism. The inhibition of ACC has demonstrated promising therapeutic potential for treating obesity and type 2 diabetes mellitus in transgenic mice and preclinical animal models. We describe herein the structure-based design and synthesis of a novel series of disubstituted (4-piperidinyl)-piperazine derivatives as ACC inhibitors. Our structure-based approach led to the discovery of the indole derivatives 13i and 13j, which exhibited potent in vitro ACC inhibitory activity.
Subject(s)
Acetyl-CoA Carboxylase/antagonists & inhibitors , Drug Design , Enzyme Inhibitors/pharmacology , Piperazines/pharmacology , Piperidines/pharmacology , Crystallography, X-Ray , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Models, Molecular , Molecular Structure , Piperazines/chemical synthesis , Piperazines/chemistry , Piperidines/chemical synthesis , Piperidines/chemistry , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Acetyl-CoA carboxylases (ACCs), the rate limiting enzymes in de novo lipid synthesis, play important roles in modulating energy metabolism. The inhibition of ACC has demonstrated promising therapeutic potential for treating obesity and type 2 diabetes mellitus in transgenic mice and preclinical animal models. We describe herein the synthesis and structure-activity relationships of a series of disubstituted (4-piperidinyl)-piperazine derivatives as a new platform for ACC1/2 non-selective inhibitors.
