ABSTRACT
Continuing our interest in designing compounds preferentially potent and selective for MMP-13, we report on a series of hydroxamic acids with a flexible amide P1' substituents. We identify an amide which spares both MMP-1 and -14, and shows >500 fold selectivity for MMP-13 versus MMP-2 and -8.
Subject(s)
Amides/chemical synthesis , Hydroxamic Acids/chemical synthesis , Matrix Metalloproteinase Inhibitors , Protease Inhibitors/chemical synthesis , Amides/chemistry , Humans , Hydroxamic Acids/chemistry , Inhibitory Concentration 50 , Molecular Structure , Protease Inhibitors/chemistry , Structure-Activity Relationship , Substrate SpecificityABSTRACT
Seeking compounds preferentially potent and selective for MMP-13, we reported in the preceding Letter on a series of hydroxamic acids with a flexible benzamide tail groups.(1a) Here, we replace the amide moiety with non-hydrolyzable heterocycles in an effort to improve half-life. We identify a hydroxamate tetrazole 4e that spares MMP-1 and -14, shows >400-fold selectivity versus MMP-8 and >600-fold selectivity versus MMP-2, and has a 4.8 h half-life in rats. X-ray data (1.9 Å) for tetrazole 4c is presented.
Subject(s)
Amides/chemical synthesis , Enzyme Inhibitors/chemical synthesis , Heterocyclic Compounds/chemical synthesis , Hydroxamic Acids/chemical synthesis , Matrix Metalloproteinase Inhibitors , Sulfones/chemical synthesis , Amides/chemistry , Animals , Crystallography, X-Ray , Enzyme Inhibitors/chemistry , Heterocyclic Compounds/chemistry , Hydroxamic Acids/chemistry , Matrix Metalloproteinase 13/chemistry , Models, Molecular , Rats , Structure-Activity Relationship , Substrate Specificity , Sulfones/chemistryABSTRACT
α-Sulfone-α-piperidine and α-tetrahydropyranyl hydroxamates were explored that are potent inhibitors of MMP's-2, -9, and -13 that spare MMP-1, with oral efficacy in inhibiting tumor growth in mice and left-ventricular hypertrophy in rats and in the bovine cartilage degradation ex vivo explant system. α-Piperidine 19v (SC-78080/SD-2590) was selected for development toward the initial indication of cancer, while α-piperidine and α-tetrahydropyranyl hydroxamates 19w (SC-77964) and 9i (SC-77774), respectively, were identified as backup compounds.
Subject(s)
Anti-Inflammatory Agents/chemical synthesis , Antineoplastic Agents/chemical synthesis , Cardiovascular Agents/chemical synthesis , Hydroxamic Acids/chemical synthesis , Matrix Metalloproteinase Inhibitors , Piperidines/chemical synthesis , Pyrans/chemical synthesis , Sulfones/chemical synthesis , Animals , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Biological Availability , Cardiovascular Agents/chemistry , Cardiovascular Agents/pharmacology , Cartilage, Articular/drug effects , Cartilage, Articular/pathology , Cattle , Crystallography, X-Ray , Humans , Hydroxamic Acids/chemistry , Hydroxamic Acids/pharmacology , Hypertrophy, Left Ventricular/drug therapy , Macaca fascicularis , Mice , Mice, Nude , Models, Molecular , Molecular Structure , Piperidines/chemistry , Piperidines/pharmacology , Pyrans/chemistry , Pyrans/pharmacology , Rats , Structure-Activity Relationship , Sulfones/chemistry , Sulfones/pharmacology , Xenograft Model Antitumor AssaysABSTRACT
Novel piperidine and piperazine derivatives have been designed and tested as inhibitors of LTA(4) hydrolase (LTA(4)H). Most potent compounds showed good potency in both enzymatic and functional human whole blood assay. Crystallography studies further confirmed observed structure-activity relationship and LTA(4)H binding mode for analogs from the piperidine series.
Subject(s)
Anti-Inflammatory Agents/chemistry , Enzyme Inhibitors/chemistry , Epoxide Hydrolases/antagonists & inhibitors , Piperazines/chemistry , Piperidines/chemistry , Anti-Inflammatory Agents/chemical synthesis , Anti-Inflammatory Agents/pharmacology , Binding Sites , Crystallography, X-Ray , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Epoxide Hydrolases/metabolism , Humans , Piperazine , Piperazines/chemical synthesis , Piperazines/pharmacology , Piperidines/chemical synthesis , Piperidines/pharmacology , Structure-Activity RelationshipABSTRACT
Proximal spinal muscular atrophy (SMA) is an autosomal recessive disorder characterized by death of motor neurons in the spinal cord that is caused by deletion and/or mutation of the survival motor neuron gene ( SMN1). Adjacent to SMN1 are a variable number of copies of the SMN2 gene. The two genes essentially differ by a single nucleotide, which causes the majority of the RNA transcripts from SMN2 to lack exon 7. Although both SMN1 and SMN2 encode the same Smn protein amino acid sequence, the loss of SMN1 and incorrect splicing of SMN2 have the consequence that Smn protein levels are insufficient for the survival of motor neurons. The therapeutic goal of our medicinal chemistry effort was to identify small-molecule activators of the SMN2 promoter that, by up-regulating gene transcription, would produce greater quantities of full-length Smn protein. Our initial medicinal chemistry effort explored a series of C5 substituted benzyl ether based 2,4-diaminoquinazoline derivatives that were found to be potent activators of the SMN2 promoter; however, inhibition of DHFR was shown to be an off-target activity that was linked to ATP depletion. We used a structure-guided approach to overcome DHFR inhibition while retaining SMN2 promoter activation. A lead compound 11a was identified as having high potency (EC50 = 4 nM) and 2.3-fold induction of the SMN2 promoter. Compound 11a possessed desirable pharmaceutical properties, including excellent brain exposure and long brain half-life following oral dosing to mice. The piperidine compound 11a up-regulated expression of the mouse SMN gene in NSC-34 cells, a mouse motor neuron hybrid cell line. In type 1 SMA patient fibroblasts, compound 11a induced Smn in a dose-dependent manner when analyzed by immunoblotting and increased the number of intranuclear particles called gems. The compound restored gems numbers in type I SMA patient fibroblasts to levels near unaffected genetic carriers of SMA.
Subject(s)
Aminoquinolines/chemical synthesis , Cyclic AMP Response Element-Binding Protein/genetics , Muscular Atrophy, Spinal/drug therapy , Nerve Tissue Proteins/genetics , Piperidines/chemical synthesis , Promoter Regions, Genetic , Quinazolines/chemical synthesis , RNA-Binding Proteins/genetics , Aminoquinolines/pharmacokinetics , Aminoquinolines/pharmacology , Animals , Biological Availability , Blood-Brain Barrier/metabolism , Cell Line , Cells, Cultured , Fibroblasts/drug effects , Fibroblasts/metabolism , Folic Acid Antagonists/chemical synthesis , Folic Acid Antagonists/chemistry , Heterozygote , Humans , Mice , Models, Molecular , Molecular Conformation , Permeability , Piperidines/pharmacokinetics , Piperidines/pharmacology , Quinazolines/pharmacokinetics , Quinazolines/pharmacology , SMN Complex Proteins , Spinal Muscular Atrophies of Childhood/genetics , Spinal Muscular Atrophies of Childhood/pathology , Stereoisomerism , Structure-Activity Relationship , Survival of Motor Neuron 1 Protein , Survival of Motor Neuron 2 Protein , Tetrahydrofolate Dehydrogenase/chemistryABSTRACT
alpha-Piperidine-beta-sulfone hydroxamate derivatives were explored that are potent for matrix metalloproteinases (MMP)-2, -9, and -13 and are sparing of MMP-1. The investigation of the beta-sulfones subsequently led to the discovery of hitherto unknown alpha-sulfone hydroxamates that are superior to the corresponding beta-sulfones in potency for target MMPs, selectivity vs MMP-1, and exposure when dosed orally. alpha-Piperidine-alpha-sulfone hydroxamate 35f (SC-276) was advanced through antitumor and antiangiogenesis assays and was selected for development. Compound 35f demonstrates excellent antitumor activity vs MX-1 breast tumor in mice when dosed orally as monotherapy or in combination with paclitaxel.
