ABSTRACT
Modification of the biphenyl portion of MMP inhibitor 2a gave analogue 2i which is greater than 1000-fold selective against MMP-2 versus MMP-1. The stereospecific synthesis of both enantiomers of 2i was achieved beginning with (S)- or (R)-benzyl glycidyl ether. The (S)-enantiomer, 11 (ABT-770), is orally bioavailable and efficacious in an in vivo model of tumor growth.
Subject(s)
Biphenyl Compounds/pharmacokinetics , Hydroxamic Acids/pharmacokinetics , Matrix Metalloproteinase Inhibitors , Administration, Oral , Animals , Antineoplastic Agents/blood , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacokinetics , Area Under Curve , Biological Availability , Biphenyl Compounds/blood , Biphenyl Compounds/chemical synthesis , Cell Division/drug effects , Dogs , Enzyme Inhibitors/blood , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacokinetics , Half-Life , Haplorhini , Hydroxamic Acids/blood , Hydroxamic Acids/chemical synthesis , Inhibitory Concentration 50 , Injections, Intravenous , Metabolic Clearance Rate , Neoplasms, Experimental/drug therapy , Rats , Structure-Activity Relationship , Tumor Cells, CulturedABSTRACT
Two series of compounds synthesized as specific matrix metalloproteinase (MMP) inhibitors have been evaluated for their inhibition of non-MMPs. In a series of substituted succinyl hydroxamic acids, some were found to be significant (IC50 < 1 microM) inhibitors of leucine (microsomal) aminopeptidase, neprilysin (3.4.24.11), and thermolysin. Macrocyclic compounds in which the alpha carbon of the succinyl hydroxamate is linked to the side chain of the P2' amino acid were found to be good inhibitors of aminopeptidase, but not of neprilysin or thermolysin. Compounds of neither series were found to be significant inhibitors of angiotensin converting enzyme or carboxypeptidase A.
Subject(s)
Matrix Metalloproteinase Inhibitors , Metalloendopeptidases/antagonists & inhibitors , Angiotensin-Converting Enzyme Inhibitors , Animals , Bacterial Proteins , Carboxypeptidases/antagonists & inhibitors , Carboxypeptidases A , Cattle , Hydroxamic Acids/chemical synthesis , Hydroxamic Acids/metabolism , Inhibitory Concentration 50 , Leucyl Aminopeptidase/antagonists & inhibitors , Neprilysin/antagonists & inhibitors , Protease Inhibitors/chemical synthesis , Protease Inhibitors/chemistry , Protease Inhibitors/metabolism , Rabbits , Rats , Swine , Thermolysin/antagonists & inhibitors , Zinc/metabolismABSTRACT
Studies conducted with the goal of discovering a second-generation platelet-activating factor (PAF) antagonist have identified a novel class of potent and orally active antagonists which have high aqueous solubility and long duration of action in animal models. The compounds arose from the combination of the lipophilic indole portion of Abbott's first-generation PAF antagonist ABT-299 (2) with the methylimidazopyridine heterocycle moiety of British Biotechnology's BB-882 (1) and possess the positive attributes of both of these clinical candidates. Structure-activity relationship (SAR) studies indicated that modification of the indole and benzoyl spacer of lead compound 7b gave analogues that were more potent, longer-lived, and bioavailable and resulted in the identification of 1-(N, N-dimethylcarbamoyl)-4-ethynyl-3-[3-fluoro-4-[(1H-2-methylimidazo[4,5-c] pyrid-1-yl)methyl]benzoyl]indole hydrochloride (ABT-491, 22 m.HCl) which has been evaluated extensively and is currently in clinical development.
Subject(s)
Imidazoles/chemical synthesis , Platelet Activating Factor/antagonists & inhibitors , Platelet Aggregation Inhibitors/chemical synthesis , Platelet Membrane Glycoproteins/metabolism , Pyridines/chemical synthesis , Receptors, Cell Surface , Receptors, G-Protein-Coupled , Animals , Biological Availability , Blood Platelets/drug effects , Blood Platelets/physiology , Capillary Permeability/drug effects , Dogs , Female , Guinea Pigs , Humans , Imidazoles/chemistry , Imidazoles/pharmacology , Macaca fascicularis , Male , Molecular Structure , Platelet Activating Factor/pharmacology , Platelet Aggregation Inhibitors/chemistry , Platelet Aggregation Inhibitors/pharmacokinetics , Platelet Aggregation Inhibitors/pharmacology , Pyridines/chemistry , Pyridines/pharmacokinetics , Pyridines/pharmacology , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
A series of succinate-derived hydroxamic acids incorporating a macrocyclic ring were designed, synthesized, and evaluated as inhibitors of matrix metalloproteinases. The inhibitors were designed based on the published X-ray crystal structure of batimastat (1) complexed with human neutrophil collagenase (MMP-8). The synthesized compounds were shown to inhibit selected MMPs in vitro with low nanomolar potency.
Subject(s)
Collagenases/chemistry , Hydroxamic Acids/chemical synthesis , Matrix Metalloproteinase Inhibitors , Phenylalanine/analogs & derivatives , Protease Inhibitors/chemical synthesis , Thiophenes/chemistry , Thiophenes/chemical synthesis , Crystallography, X-Ray , Drug Design , Humans , Hydroxamic Acids/chemistry , Hydroxamic Acids/pharmacology , Indicators and Reagents , Kinetics , Matrix Metalloproteinase 8 , Models, Molecular , Phenylalanine/chemistry , Phenylalanine/pharmacology , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , Structure-Activity Relationship , Succinates/chemical synthesis , Succinates/chemistry , Succinates/pharmacology , Thiophenes/pharmacologyABSTRACT
(2RS,4R)-3-(2-(3-Pyridinyl)thiazolidin-4-oyl)indoles represent a new class of potent, orally active antagonists of platelet activating factor (PAF). The compounds were prepared by acylation of the magnesium or zinc salts of substituted indoles with (2RS,4R)-2-(3-pyridinyl)-3-(tert-butoxycarbonyl)thiazolidin-4-oyl chloride. The 3-acylindole moiety functions as a hydrolytically stabilized and conformationally restricted anilide replacement, which imparts a considerable boost in potency to the series. Structure-activity relationships observed for substitution on the indole ring system are discussed. Members of the series compare favorably with other reported PAF antagonists.
Subject(s)
Capillary Permeability/drug effects , Edema/drug therapy , Indoles/pharmacology , Platelet Activating Factor/antagonists & inhibitors , Thiazoles/pharmacology , Administration, Oral , Animals , Edema/chemically induced , In Vitro Techniques , Indoles/chemical synthesis , Indoles/chemistry , Indoles/therapeutic use , Magnetic Resonance Spectroscopy , Male , Mice , Rabbits , Rats , Rats, Sprague-Dawley , Serotonin/blood , Skin/drug effects , Skin/metabolism , Stereoisomerism , Structure-Activity Relationship , Thiazoles/chemical synthesis , Thiazoles/chemistry , Thiazoles/therapeutic useABSTRACT
In the male retired breeder rat, arachidonic acid 1a and 2,2-dimethylarachidonic acid 3a exhibited plasma platelet disaggregation as measured after 3 hr after the compounds were administered intragastrically at 15 and 13 mg/kg/rat mean effective dose (MED), respectively. The corresponding p-t-butylphenol ester of the acids showed a remarkable potentiation of platelet disaggregation. The MED for p-t-butylphenol ester of AA was 1.1 mg/kg/rat.
