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1.
Bioorg Med Chem Lett ; 22(8): 2670-4, 2012 Apr 15.
Article in English | MEDLINE | ID: mdl-22450130

ABSTRACT

The design and optimization of a novel isoxazole S(1) linker for renin inhibitor is described herein. This effort culminated in the identification of compound 18, an orally bioavailable, sub-nanomolar renin inhibitor even in the presence of human plasma. When compound 18 was found to inhibit CYP3A4 in a time dependent manner, two strategies were pursued that successfully delivered equipotent compounds with minimal TDI potential.


Subject(s)
Antihypertensive Agents/chemistry , Drug Design , Isoxazoles/chemistry , Isoxazoles/chemical synthesis , Renin/antagonists & inhibitors , Administration, Oral , Animals , Antihypertensive Agents/chemical synthesis , Antihypertensive Agents/pharmacology , Catalytic Domain , Enzyme Activation/drug effects , Humans , Isoxazoles/pharmacology , Molecular Structure , Rats , Structure-Activity Relationship
2.
Bioorg Med Chem Lett ; 21(13): 3976-81, 2011 Jul 01.
Article in English | MEDLINE | ID: mdl-21641209

ABSTRACT

The design and optimization of a novel series of renin inhibitor is described herein. Strategically, by committing the necessary resources to the development of synthetic sequences and scaffolds that were most amenable for late stage structural diversification, even as the focus of the SAR campaign moved from one end of the molecule to another, highly potent renin inhibitors could be rapidly identified and profiled.


Subject(s)
Alcohols/chemical synthesis , Antihypertensive Agents/chemical synthesis , Antihypertensive Agents/therapeutic use , Drug Design , Hypertension/drug therapy , Piperidines/chemical synthesis , Renin/antagonists & inhibitors , Alcohols/chemistry , Alcohols/therapeutic use , Animals , Antihypertensive Agents/chemistry , Molecular Structure , Piperidines/chemistry , Piperidines/therapeutic use , Rats , Renin/chemistry , Structure-Activity Relationship
3.
Bioorg Med Chem Lett ; 21(13): 3970-5, 2011 Jul 01.
Article in English | MEDLINE | ID: mdl-21621998

ABSTRACT

An SAR campaign aimed at decreasing the overall lipophilicity of renin inhibitors such as 1 is described herein. It was found that replacement of the northern appendage in 1 with an N-methyl pyridone and subsequent re-optimization of the benzyl amide handle afforded compounds with in vitro and in vivo profiles suitable for further profiling. An unexpected CV toxicity in dogs observed with compound 20 led to the employment of a time and resource sparing rodent model for in vivo screening of key compounds. This culminated in the identification of compound 31 as an optimized renin inhibitor.


Subject(s)
Drug Design , Hypertension/drug therapy , Piperidines/chemical synthesis , Pyridones/chemical synthesis , Renin/antagonists & inhibitors , Animals , Dogs , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Inhibitory Concentration 50 , Models, Molecular , Molecular Structure , Piperidines/chemistry , Piperidines/therapeutic use , Pyridones/chemistry , Pyridones/therapeutic use , Rats , Structure-Activity Relationship
4.
J Renin Angiotensin Aldosterone Syst ; 12(3): 133-45, 2011 Sep.
Article in English | MEDLINE | ID: mdl-21393355

ABSTRACT

INTRODUCTION: The hypertensive double-transgenic (dTG) rat strain, expressing human renin and angiotensinogen, develops severe hypertension and organ damage and 50% of individuals die by 7 weeks of age. Here, we characterise a variation of this model in which animals present stable hypertension. MATERIALS AND METHODS: The effect of renin-angiotensin system blockers on blood pressure was determined with adult dTG rats treated with enalapril from 3 to 12 weeks of age. Tissue expression levels of renin and angiotensinogen were determined in dTG rats and rhesus monkeys by quantitative PCR. RESULTS: Upon withdrawal from enalapril, mean arterial pressure (MAP) rose to 160-180 mmHg, with 95% of the female dTG rats surviving for 6 to 12 months, In Sprague-Dawley (SD) rats and rhesus monkeys, renin mRNA was absent or weakly expressed in most tissues, except for the kidneys and adrenals. In dTG rats, human renin expression was high in many additional tissues. The expression of human angiotensinogen in dTG rats followed a similar tissue pattern to SD and rhesus monkey angiotensinogen. Oral dosing of aliskiren, enalapril or losartan provided a similar maximal reduction in MAP and duration of efficacy in telemetrised dTG rats. CONCLUSIONS: Enalapril-pretreated dTG rats are suitable for long-term MAP monitoring and sequential evaluation of human renin inhibitors.


Subject(s)
Enalapril/pharmacology , Enalapril/therapeutic use , Hypertension/drug therapy , Renin/antagonists & inhibitors , Amides/administration & dosage , Amides/pharmacology , Amides/therapeutic use , Angiotensinogen/genetics , Angiotensinogen/metabolism , Animals , Blood Pressure/drug effects , Disease Models, Animal , Enalapril/administration & dosage , Female , Fumarates/administration & dosage , Fumarates/pharmacology , Fumarates/therapeutic use , Gene Expression Regulation/drug effects , Heart Rate/drug effects , Humans , Hypertension/physiopathology , Macaca mulatta , RNA, Messenger/genetics , RNA, Messenger/metabolism , Rats , Rats, Sprague-Dawley , Rats, Transgenic , Renin/blood , Renin/genetics , Tissue Distribution/drug effects
5.
Biol Chem ; 391(12): 1469-73, 2010 Dec.
Article in English | MEDLINE | ID: mdl-20868234

ABSTRACT

Renin is the first enzyme in the renin-angiotensin-aldosterone system which is the principal regulator of blood pressure and hydroelectrolyte balance. Previous studies suggest that cathepsin B is the activator of the prorenin zymogen. Here, we show no difference in plasma renin activity, or mean arterial blood pressure between wild-type and cathepsin B knockout mice. To account for potential gene compensation, a potent, selective, reversible cathepsin B inhibitor was developed to determine the role of cathepsin B on prorenin processing in rats. Pharmacological inhibition of cathepsin B in spontaneously hypertensive and double transgenic rats did not result in a reduction in renal mature renin protein levels or plasma renin activity. We conclude that cathepsin B does not play a significant role in this process in rodents.


Subject(s)
Cathepsin B/physiology , Renin/metabolism , Animals , Cathepsin B/antagonists & inhibitors , Cathepsin B/genetics , Enzyme Inhibitors/pharmacology , Hypertension/genetics , Hypertension/metabolism , Mice , Mice, Knockout , Rats , Rats, Transgenic
6.
Bioorg Med Chem Lett ; 20(7): 2204-9, 2010 Apr 01.
Article in English | MEDLINE | ID: mdl-20206513

ABSTRACT

The discovery and SAR of a new series of substituted amino propanamide renin inhibitors are herein described. This work has led to the preparation of compounds with in vitro and in vivo profiles suitable for further development. Specifically, challenges pertaining to oral bioavailability, covalent binding and time-dependent CYP 3A4 inhibition were overcome thereby culminating in the identification of compound 50 as an optimized renin inhibitor with good efficacy in the hypertensive double-transgenic rat model.


Subject(s)
Antihypertensive Agents/chemistry , Antihypertensive Agents/therapeutic use , Hypertension/drug therapy , Renin/antagonists & inhibitors , Renin/metabolism , Animals , Antihypertensive Agents/pharmacology , Blood Pressure/drug effects , Crystallography, X-Ray , Dogs , Humans , Models, Molecular , Protein Binding , Rats , Rats, Sprague-Dawley , Renin/chemistry , Structure-Activity Relationship
7.
J Med Chem ; 48(24): 7535-43, 2005 Dec 01.
Article in English | MEDLINE | ID: mdl-16302795

ABSTRACT

The lysosomal cysteine protease cathepsin K is a target for osteoporosis therapy. The aryl-piperazine-containing cathepsin K inhibitor CRA-013783/L-006235 (1) displays greater than 4000-fold selectivity against the lysosomal/endosomal antitargets cathepsin B, L, and S. However, 1 and other aryl-piperazine-containing analogues, including balicatib (10), are approximately 10-100-fold more potent in cell-based enzyme occupancy assays than against each purified enzyme. This phenomenon arises from their basic, lipophilic nature, which results in lysosomal trapping. Consistent with its lysosomotropic nature, 1 accumulates in cells and in rat tissues of high lysosome content. In contrast, nonbasic aryl-morpholino-containing analogues do not exhibit lysosomotropic properties. Increased off-target activities of basic cathepsin K inhibitors were observed in a cell-based cathepsin S antigen presentation assay. No potency increases of basic inhibitors in a functional cathepsin K bone resorption whole cell assay were detected. Therefore, basic cathepsin K inhibitors, such as 1, suffer from reduced functional selectivities compared to those predicted using purified enzyme assays.


Subject(s)
Benzamides/pharmacology , Cathepsins/antagonists & inhibitors , Lysosomes/drug effects , Morpholines/pharmacology , Piperazines/pharmacology , Thiazoles/pharmacology , Animals , Antigen Presentation/drug effects , Autoradiography , Benzamides/chemistry , Benzamides/pharmacokinetics , Bone Density Conservation Agents/chemistry , Bone Density Conservation Agents/pharmacokinetics , Bone Density Conservation Agents/pharmacology , Cathepsin B/antagonists & inhibitors , Cathepsin K , Cathepsin L , Cell Line , Cysteine Endopeptidases , Female , Humans , Lysosomes/enzymology , Mice , Mice, Inbred C57BL , Morpholines/chemistry , Piperazines/chemistry , Piperazines/pharmacokinetics , Rabbits , Rats , Structure-Activity Relationship , Thiazoles/chemistry , Thiazoles/pharmacokinetics , Tissue Distribution
8.
J Biol Chem ; 279(27): 27905-14, 2004 Jul 02.
Article in English | MEDLINE | ID: mdl-15067000

ABSTRACT

Apoptotic markers consist of either caspase substrate cleavage products or phenotypic changes that manifest themselves as a consequence of caspase-mediated substrate cleavage. We have shown recently that pharmacological inhibitors of caspase activity prevent the appearance of two such apoptotic manifestations, alphaII-spectrin cleavage and DNA fragmentation, but that blockade of the latter required a significantly higher concentration of inhibitor. We investigated this phenomenon through the use of a novel radiolabeled caspase inhibitor, [(125)I]M808, which acts as a caspase active site probe. [(125)I]M808 bound to active caspases irreversibly and with high sensitivity in apoptotic cell extracts, in tissue extracts from several commonly used animal models of cellular injury, and in living cells. Moreover, [(125)I]M808 detected active caspases in septic mice when injected intravenously. Using this caspase probe, an active site occupancy assay was developed and used to measure the fractional inhibition required to block apoptosis-induced DNA fragmentation. In thymocytes, occupancy of up to 40% of caspase active sites had no effect on DNA fragmentation, whereas inhibition of half of the DNA cleaving activity required between 65 and 75% of active site occupancy. These results suggest that a high and persistent fractional inhibition will be required for successful caspase inhibition-based therapies.


Subject(s)
Caspases/chemistry , DNA Fragmentation , Amino Acid Chloromethyl Ketones/pharmacology , Animals , Apoptosis , Binding Sites , Blotting, Western , Caspase Inhibitors , Cecum/pathology , Coculture Techniques , Dose-Response Relationship, Drug , Electrophoresis, Polyacrylamide Gel , Enzyme Inhibitors/pharmacology , Female , Humans , Inhibitory Concentration 50 , Iodine Radioisotopes/metabolism , Jurkat Cells , Kinetics , Mice , Models, Chemical , Protein Binding , Rats , Rats, Sprague-Dawley , Sensitivity and Specificity , Sepsis , Thymus Gland/cytology , Tissue Distribution
9.
Br J Pharmacol ; 141(4): 689-97, 2004 Feb.
Article in English | MEDLINE | ID: mdl-14744804

ABSTRACT

1. Caspases, key enzymes in the apoptosis pathway, have been detected in the brain of HD patients and in animal models of the disease. In the present study, we investigated the neuroprotective properties of a new, reversible, caspase-3-specific inhibitor, M826 (3-([(2S)-2-[5-tert-butyl-3-[[(4-methyl-1,2,5-oxadiazol-3-yl)methyl]amino]-2-oxopyrazin-1(2H)-yl]butanoyl]amino)-5-[hexyl(methyl)amino]-4-oxopentanoic acid), in a rat malonate model of HD. 2. Pharmacokinetic and autoradiography studies after intrastriatal (i.str.) injection of 1.5 nmol of M826 or its tritiated analogue [(3)H]M826 indicated that the compound diffused within the entire striatum. The elimination half-life (T(1/2)) of M826 in the rat striatum was 3 h. 3. I.str. injection of 1.5 nmol of M826 10 min after malonate infusion induced a significant reduction (66%) in the number of neurones expressing active caspase-3 in the ipsilateral striatum. 4. Inhibition of active caspase-3 translated into a significant but moderate reduction (39%) of the lesion volume, and of cell death (24%), 24 h after injury. The efficacy of M826 at inhibiting cell death was comparable to that of the noncompetitive NMDA receptor antagonist MK801. 5. These data provide in vivo proof-of-concept of the neuroprotective effects of reversible caspase-3 inhibitors in a model of malonate-induced striatal injury in the adult rat.


Subject(s)
Caspase Inhibitors , Enzyme Inhibitors/pharmacology , Huntington Disease/chemically induced , Huntington Disease/drug therapy , Malonates , Neuroprotective Agents , Oxadiazoles/pharmacology , Pyrazines/pharmacology , Animals , Autoradiography , Caspase 3 , Cell Count , Cell Death/drug effects , Diffusion , Dizocilpine Maleate/pharmacology , Enzyme Inhibitors/pharmacokinetics , Enzyme-Linked Immunosorbent Assay , Excitatory Amino Acid Antagonists/pharmacology , Half-Life , Huntington Disease/pathology , Male , Neostriatum/pathology , Neurons/drug effects , Oxadiazoles/pharmacokinetics , Pyrazines/pharmacokinetics , Rats , Rats, Sprague-Dawley
10.
J Exp Med ; 199(2): 199-207, 2004 Jan 19.
Article in English | MEDLINE | ID: mdl-14718517

ABSTRACT

A rodent model of sepsis was used to establish the relationship between caspase inhibition and inhibition of apoptotic cell death in vivo. In this model, thymocyte cell death was blocked by Bcl-2 transgene, indicating that apoptosis was predominantly dependent on the mitochondrial pathway that culminates in caspase-3 activation. Caspase inhibitors, including the selective caspase-3 inhibitor M867, were able to block apoptotic manifestations both in vitro and in vivo but with strikingly different efficacy for different cell death markers. Inhibition of DNA fragmentation required substantially higher levels of caspase-3 attenuation than that required for blockade of other apoptotic events such as spectrin proteolysis and phosphatidylserine externalization. These data indicate a direct relationship between caspase inhibition and some apoptotic manifestations but that small quantities of uninhibited caspase-3 suffice to initiate genomic DNA breakdown, presumably through the escape of catalytic quantities of caspase-activated DNase. These findings suggest that putative caspase-independent apoptosis may be overestimated in some systems since blockade of spectrin proteolysis and other cell death markers does not accurately reflect the high degrees of caspase-3 inhibition needed to prevent DNA fragmentation. Furthermore, this requirement presents substantial therapeutic challenges owing to the need for persistent and complete caspase blockade.


Subject(s)
Apoptosis/drug effects , Caspase Inhibitors , Cysteine Proteinase Inhibitors/pharmacology , Oxadiazoles/pharmacology , Pyrazines/pharmacology , Sepsis/drug therapy , Sepsis/pathology , Animals , Biomarkers , Caspase 3 , DNA Fragmentation/drug effects , Female , Genes, bcl-2 , Mice , Mice, Inbred C57BL , Mice, Transgenic , Rats , Rats, Sprague-Dawley , Sepsis/enzymology , Sepsis/genetics , Spectrin/metabolism , T-Lymphocytes/drug effects , T-Lymphocytes/enzymology , T-Lymphocytes/pathology
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