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1.
J Biol Chem ; 290(33): 20044-59, 2015 Aug 14.
Article in English | MEDLINE | ID: mdl-26085101

ABSTRACT

Insulin-degrading enzyme (IDE, insulysin) is the best characterized catabolic enzyme implicated in proteolysis of insulin. Recently, a peptide inhibitor of IDE has been shown to affect levels of insulin, amylin, and glucagon in vivo. However, IDE(-/-) mice display variable phenotypes relating to fasting plasma insulin levels, glucose tolerance, and insulin sensitivity depending on the cohort and age of animals. Here, we interrogated the importance of IDE-mediated catabolism on insulin clearance in vivo. Using a structure-based design, we linked two newly identified ligands binding at unique IDE exosites together to construct a potent series of novel inhibitors. These compounds do not interact with the catalytic zinc of the protease. Because one of these inhibitors (NTE-1) was determined to have pharmacokinetic properties sufficient to sustain plasma levels >50 times its IDE IC50 value, studies in rodents were conducted. In oral glucose tolerance tests with diet-induced obese mice, NTE-1 treatment improved the glucose excursion. Yet in insulin tolerance tests and euglycemic clamp experiments, NTE-1 did not enhance insulin action or increase plasma insulin levels. Importantly, IDE inhibition with NTE-1 did result in elevated plasma amylin levels, suggesting the in vivo role of IDE action on amylin may be more significant than an effect on insulin. Furthermore, using the inhibitors described in this report, we demonstrate that in HEK cells IDE has little impact on insulin clearance. In total, evidence from our studies supports a minimal role for IDE in insulin metabolism in vivo and suggests IDE may be more important in helping regulate amylin clearance.


Subject(s)
Enzyme Inhibitors/pharmacology , Insulin/metabolism , Insulysin/antagonists & inhibitors , Animals , Binding Sites , Crystallography, X-Ray , Enzyme Inhibitors/pharmacokinetics , HEK293 Cells , Humans , Insulysin/chemistry , Models, Molecular , Proteolysis
2.
Bioorg Med Chem Lett ; 25(5): 998-1008, 2015 Mar 01.
Article in English | MEDLINE | ID: mdl-25630223

ABSTRACT

The pharmaceutical industry is currently facing multiple challenges, in particular the low number of new drug approvals in spite of the high level of R&D investment. In order to improve target selection and assess properly the clinical hypothesis, it is important to start building an integrated drug discovery approach during Lead Generation. This should include special emphasis on evaluating target engagement in the target tissue and linking preclinical to clinical readouts. In this review, we would like to illustrate several strategies and technologies for assessing target engagement and the value of its application to medicinal chemistry efforts.


Subject(s)
Drug Delivery Systems/methods , Drug Discovery/methods , Animals , Humans , Luminescent Measurements/methods , Optical Imaging/methods , Pharmaceutical Preparations/chemistry , Pharmaceutical Preparations/metabolism , Pharmacokinetics , Positron-Emission Tomography/methods
3.
Bioorg Med Chem ; 23(5): 996-1010, 2015 Mar 01.
Article in English | MEDLINE | ID: mdl-25661449

ABSTRACT

Trypanothione reductase (TR) is an enzyme critical to the maintenance of the thiol redox balance in trypanosomatids, including the genera Trypanosoma and Leishmania that are parasites responsible for several serious diseases. Analogs of clomipramine were prepared since clomipramine is reported to inhibit TR and cure mice infected with trypanosomes, however its psychotropic activity precludes its use as an anti-trypanosomal therapeutic. The clomipramine analogs contained a tricyclic dibenzosuberyl moiety. Additionally a series of polyamines with N-dibenzosuberyl substituents were prepared. All compounds studied were competitive inhibitors of TR and showed trypanocidal activities against Trypanosoma brucei in vitro. The analogs of clomipramine were poor inhibitors of TR, whereas the polyamine derivatives were effective TR inhibitors with the most potent compound, N(4),N(8)-bis(dibenzosuberyl)spermine (7), having a Ki value of 0.26µM. However, compound (7) did not prolong the lives of mice infected with trypanosomes. Analysis of docking studies indicated: the tricyclic groups of inhibitors bind at four distinct hydrophobic regions in the active site of TR; the importance of the chlorine substituent of clomipramine in binding to TR; and binding of the dibenzosuberyl groups of (7) occur at separate and distinct hydrophobic regions within the active site of TR.


Subject(s)
Clomipramine/analogs & derivatives , Enzyme Inhibitors/pharmacology , NADH, NADPH Oxidoreductases/antagonists & inhibitors , Polyamines/pharmacology , Trypanocidal Agents/pharmacology , Animals , Clomipramine/chemistry , Enzyme Inhibitors/chemistry , Mice , Molecular Docking Simulation , Polyamines/chemistry , Trypanosoma brucei brucei/drug effects , Trypanosoma brucei brucei/enzymology
4.
J Med Chem ; 66(23): 15960-15976, 2023 12 14.
Article in English | MEDLINE | ID: mdl-37992274

ABSTRACT

The identification of clinical candidate LY3522348 (compound 23) is described. LY3522348 is a highly selective, oral dual inhibitor of human ketohexokinase isoforms C and A (hKHK-C, hKHK-A). Optimization began with highly efficient (S)-2-(2-methylazetidin-1-yl)-6-(1H-pyrazol-4-yl)-4-(trifluoromethyl)nicotinonitrile (3). Efforts focused on developing absorption, distribution, metabolism, potency, and in vitro safety profiles to support oral QD dosing in patients. Structure-based design leveraged vectors for substitution of the pyrazole ring, which provided an opportunity to interact with several different proximal amino acid residues in the protein. LY3522348 displayed a robust pharmacodynamic response in a mouse model of fructose metabolism and was advanced into clinical trials.


Subject(s)
Fructokinases , Mice , Animals , Humans
5.
J Med Chem ; 65(20): 13892-13909, 2022 10 27.
Article in English | MEDLINE | ID: mdl-36197449

ABSTRACT

Protein tyrosine phosphatases constitute an important class of drug targets whose potential has been limited by the paucity of drug-like small-molecule inhibitors. We recently described a class of active-site-directed, moderately selective, and potent inhibitors of the low-molecular-weight protein tyrosine phosphatase (LMW-PTP). Here, we report our extensive structure-based design and optimization effort that afforded inhibitors with vastly improved potency and specificity. The leading compound inhibits LMW-PTP potently and selectively (Ki = 1.2 nM, >8000-fold selectivity). Many compounds exhibit favorable drug-like properties, such as low molecular weight, weak cytochrome P450 inhibition, high metabolic stability, moderate to high cell permeability (Papp > 0.2 nm/s), and moderate to good oral bioavailability (% F from 23 to 50% in mice), and therefore can be used as in vivo chemical probes to further dissect the complex biological as well as pathophysiological roles of LMW-PTP and for the development of therapeutics targeting LMW-PTP.


Subject(s)
Enzyme Inhibitors , Protein Tyrosine Phosphatases , Mice , Animals , Molecular Weight , Protein Tyrosine Phosphatases/metabolism , Catalytic Domain , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/chemistry
6.
EBioMedicine ; 27: 200-213, 2018 Jan.
Article in English | MEDLINE | ID: mdl-29290411

ABSTRACT

Prescription ω-3 fatty acid ethyl ester supplements are commonly used for the treatment of hypertriglyceridemia. However, the metabolic profile and effect of the metabolites formed by these treatments remain unknown. Here we utilized unbiased metabolomics to identify 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF) as a significant metabolite of the ω-3-acid ethyl ester prescription Lovaza™ in humans. Administration of CMPF to mice before or after high-fat diet feeding at exposures equivalent to those observed in humans increased whole-body lipid metabolism, improved insulin sensitivity, increased beta-oxidation, reduced lipogenic gene expression, and ameliorated steatosis. Mechanistically, we find that CMPF acutely inhibits ACC activity, and induces long-term loss of SREBP1c and ACC1/2 expression. This corresponds to an induction of FGF21, which is required for long-term steatosis protection, as FGF21KO mice are refractory to the improved metabolic effects. Thus, CMPF treatment in mice parallels the effects of human Lovaza™ supplementation, revealing that CMPF may contribute to the improved metabolic effects observed with ω-3 fatty acid prescriptions.


Subject(s)
Dietary Supplements , Esters/therapeutic use , Fatty Acids, Omega-3/therapeutic use , Fatty Liver/drug therapy , Fatty Liver/prevention & control , Furans/therapeutic use , Metabolome , Propionates/therapeutic use , Adult , Animals , Diet, High-Fat , Dose-Response Relationship, Drug , Fatty Liver/metabolism , Fatty Liver/pathology , Female , Fibroblast Growth Factors/deficiency , Fibroblast Growth Factors/metabolism , Furans/metabolism , Humans , Insulin Resistance , Lipid Metabolism , Liver/metabolism , Liver/pathology , Male , Mice , Mice, Knockout , Mice, Obese , Propionates/metabolism
7.
Sci Rep ; 8(1): 15458, 2018 10 18.
Article in English | MEDLINE | ID: mdl-30337562

ABSTRACT

AICARFT is a folate dependent catalytic site within the ATIC gene, part of the purine biosynthetic pathway, a pathway frequently upregulated in cancers. LSN3213128 is a potent (16 nM) anti-folate inhibitor of AICARFT and selective relative to TS, SHMT1, MTHFD1, MTHFD2 and MTHFD2L. Increases in ZMP, accompanied by activation of AMPK and cell growth inhibition, were observed with treatment of LY3213128. These effects on ZMP and proliferation were dependent on folate levels. In human breast MDA-MB-231met2 and lung NCI-H460 cell lines, growth inhibition was rescued by hypoxanthine, but not in the A9 murine cell line which is deficient in purine salvage. In athymic nude mice, LSN3213128 robustly elevates ZMP in MDA-MB-231met2, NCI-H460 and A9 tumors in a time and dose dependent manner. Significant tumor growth inhibition in human breast MDA-MB231met2 and lung NCI-H460 xenografts and in the syngeneic A9 tumor model were observed with oral administration of LSN3213128. Strikingly, AMPK appeared activated within the tumors and did not change even at high levels of intratumoral ZMP after weeks of dosing. These results support the evaluation of LSN3213128 as an antineoplastic agent.


Subject(s)
Aminoimidazole Carboxamide/analogs & derivatives , Antineoplastic Agents , Enzyme Inhibitors/pharmacology , Hydroxymethyl and Formyl Transferases/antagonists & inhibitors , Lung Neoplasms , Multienzyme Complexes/antagonists & inhibitors , Neoplasm Proteins/antagonists & inhibitors , Nucleotide Deaminases/antagonists & inhibitors , Ribonucleotides , Aminoimidazole Carboxamide/pharmacokinetics , Aminoimidazole Carboxamide/pharmacology , Animals , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Female , Humans , Hydroxymethyl and Formyl Transferases/metabolism , Lung Neoplasms/drug therapy , Lung Neoplasms/enzymology , Lung Neoplasms/pathology , Mice , Mice, Nude , Multienzyme Complexes/metabolism , Neoplasm Proteins/metabolism , Nucleotide Deaminases/metabolism , Ribonucleotides/pharmacokinetics , Ribonucleotides/pharmacology , Xenograft Model Antitumor Assays
8.
J Med Chem ; 60(13): 5933-5939, 2017 07 13.
Article in English | MEDLINE | ID: mdl-28613895

ABSTRACT

Aggrecanase-1 and -2 (ADAMTS-4 and ADAMTS-5) are zinc metalloproteases involved in the degradation of aggrecan in cartilage. Inhibitors could provide a means of altering the progression of osteoarthritis. We report the identification of 7 which had good oral pharmacokinetics in rats and showed efficacy in a rat chemical model of osteoarthritis. The projected human dose required to achieve sustained plasma levels ≥10 times the hADAMTS-5 IC50 is 5 mg q.d.


Subject(s)
ADAMTS4 Protein/antagonists & inhibitors , ADAMTS5 Protein/antagonists & inhibitors , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/therapeutic use , Hydantoins/chemistry , Hydantoins/therapeutic use , Osteoarthritis/drug therapy , ADAMTS4 Protein/metabolism , ADAMTS5 Protein/metabolism , Aggrecans/metabolism , Animals , Enzyme Inhibitors/blood , Enzyme Inhibitors/pharmacology , Humans , Hydantoins/blood , Hydantoins/pharmacology , Male , Molecular Docking Simulation , Osteoarthritis/enzymology , Osteoarthritis/metabolism , Rats , Rats, Inbred Lew
9.
J Med Chem ; 60(5): 1860-1875, 2017 03 09.
Article in English | MEDLINE | ID: mdl-28171722

ABSTRACT

CMPF (2-(2-carboxyethyl)-4-methyl-5-propylfuran-3-carboxylic acid) is a metabolite that circulates at high concentrations in type 2 and gestational diabetes patients. Further, human clinical studies suggest it might have a causal role in these diseases. CMPF inhibits insulin secretion in mouse and human islets in vitro and in vivo in rodents. However, the metabolic fate of CMPF and the relationship of structure to effects on insulin secretion have not been significantly studied. The syntheses of CMPF and analogues are described. These include isotopically labeled molecules. Study of these materials in vivo has led to the first observation of a metabolite of CMPF. In addition, a wide range of CMPF analogues have been prepared and characterized in insulin secretion assays using both mouse and human islets. Several molecules that influence insulin secretion in vitro were identified. The molecules described should serve as interesting probes to further study the biology of CMPF.


Subject(s)
Carboxylic Acids/chemical synthesis , Carboxylic Acids/pharmacology , Furans/chemical synthesis , Furans/pharmacology , Insulin/metabolism , Animals , Cytochrome P-450 Enzyme System/metabolism , Humans , Insulin Secretion , Islets of Langerhans/drug effects , Islets of Langerhans/enzymology , Islets of Langerhans/metabolism , Mice
10.
J Med Chem ; 60(23): 9807-9820, 2017 12 14.
Article in English | MEDLINE | ID: mdl-29088532

ABSTRACT

NMR conformational analysis of a hydroxyethylamine peptide isostere developed as an aspartic protease inhibitor shows that it is a flexible architecture. Cyclization to form pyrrolidines, piperidines, or morpholines results in a preorganization of the whole system in solution. The resulting conformation is similar to the conformation of the inhibitor in the active site of BACE-1. This entropic gain results in increased affinity for the enzyme when compared with the acyclic system. For morpholines 27 and 29, the combination of steric and electronic factors is exploited to orient substituents toward S1, S1', and S2' pockets both in the solution and in the bound states. These highly preorganized molecules proved to be the most potent compounds of the series. Additionally, the morpholines, unlike the pyrrolidine and piperidine analogues, have been found to be brain penetrant BACE-1 inhibitors.


Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Aspartic Acid Endopeptidases/antagonists & inhibitors , Ethylamines/chemistry , Ethylamines/pharmacology , Peptides/chemistry , Peptides/pharmacology , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , Amyloid Precursor Protein Secretases/metabolism , Animals , Aspartic Acid Endopeptidases/metabolism , Brain/metabolism , Crystallography, X-Ray , Cyclization , Drug Design , Ethylamines/pharmacokinetics , Humans , Magnetic Resonance Spectroscopy , Mice , Models, Molecular , Morpholines/chemistry , Morpholines/pharmacokinetics , Morpholines/pharmacology , Peptides/pharmacokinetics , Protease Inhibitors/pharmacokinetics , Structure-Activity Relationship
11.
J Med Chem ; 60(23): 9599-9616, 2017 12 14.
Article in English | MEDLINE | ID: mdl-29072452

ABSTRACT

A hallmark of cancer is unbridled proliferation that can result in increased demand for de novo synthesis of purine and pyrimidine bases required for DNA and RNA biosynthesis. These synthetic pathways are frequently upregulated in cancer and involve various folate-dependent enzymes. Antifolates have a proven record as clinically used oncolytic agents. Our recent research efforts have produced LSN 3213128 (compound 28a), a novel, selective, nonclassical, orally bioavailable antifolate with potent and specific inhibitory activity for aminoimidazole-4-carboxamide ribonucleotide formyltransferase (AICARFT), an enzyme in the purine biosynthetic pathway. Inhibition of AICARFT with compound 28a results in dramatic elevation of 5-aminoimidazole 4-carboxamide ribonucleotide (ZMP) and growth inhibition in NCI-H460 and MDA-MB-231met2 cancer cell lines. Treatment with this inhibitor in a murine based xenograft model of triple negative breast cancer (TNBC) resulted in tumor growth inhibition.


Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/therapeutic use , Folic Acid Antagonists/chemistry , Folic Acid Antagonists/therapeutic use , Phosphoribosylaminoimidazolecarboxamide Formyltransferase/antagonists & inhibitors , Triple Negative Breast Neoplasms/drug therapy , Animals , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Breast/drug effects , Breast/metabolism , Breast/pathology , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Discovery , Female , Folic Acid Antagonists/pharmacokinetics , Folic Acid Antagonists/pharmacology , Humans , Male , Mice , Mice, Nude , Models, Molecular , Phosphoribosylaminoimidazolecarboxamide Formyltransferase/metabolism , Sulfonamides/chemistry , Sulfonamides/pharmacokinetics , Sulfonamides/pharmacology , Sulfonamides/therapeutic use , Thiophenes/chemistry , Thiophenes/pharmacokinetics , Thiophenes/pharmacology , Thiophenes/therapeutic use , Triple Negative Breast Neoplasms/metabolism , Triple Negative Breast Neoplasms/pathology
12.
Curr Opin Drug Discov Devel ; 9(6): 776-91, 2006 Nov.
Article in English | MEDLINE | ID: mdl-17117686

ABSTRACT

BACE (beta-site amyloid precursor protein [APP] cleavage enzyme) is a transmembrane aspartyl protease responsible for the first cleavage event in the processing of APP to Abeta peptide. Amyloid plaques composed of Abeta peptides are hypothesized to be the root cause of neuronal cell death in Alzheimer's disease patients. Thus, BACE has become a target of significant interest for pharmaceutical and academic research. The recent literature relating to the discovery and development of efficacious BACE inhibitors is reviewed with particular emphasis on the patent literature.


Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Aspartic Acid Endopeptidases/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Pharmacology, Clinical/methods , Alzheimer Disease/enzymology , Alzheimer Disease/metabolism , Alzheimer Disease/prevention & control , Amyloid Precursor Protein Secretases/adverse effects , Amyloid Precursor Protein Secretases/metabolism , Amyloid beta-Peptides/metabolism , Aspartic Acid Endopeptidases/adverse effects , Aspartic Acid Endopeptidases/metabolism , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/therapeutic use , Ethylamines/chemistry , Ethylamines/pharmacology , Ethylamines/therapeutic use , Humans , Molecular Structure , Patents as Topic/statistics & numerical data , Pharmacology, Clinical/trends
13.
J Med Chem ; 59(12): 5810-22, 2016 06 23.
Article in English | MEDLINE | ID: mdl-27194201

ABSTRACT

The development of reliable relationships between in vivo target engagement, pharmacodynamic activity, and efficacy in chronic disease models is beneficial for enabling hypothesis-driven drug discovery and facilitating the development of patient-focused candidate selection criteria. Toward those ends, osmotic infusion pumps can be useful for overcoming limitations in the PK properties of proof-of-concept (POC) compounds to accelerate the development of such relationships. In this report, we describe the application of this strategy to the development of hydantoin-derived aggrecanase inhibitors (eg, 3) for the treatment of osteoarthiritis (OA). Potent, selective inhibitors were efficacious in both chemical and surgical models of OA when exposures were sustained in excess of 10 times the plasma IC50. The use of these data for establishing patient-focused candidate selection criteria is exemplified with the characterization of compound 8, which is projected to sustain the desired level of target engagement at a dose of 45 mg qd.


Subject(s)
Endopeptidases/metabolism , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/pharmacokinetics , Hydantoins/pharmacology , Hydantoins/pharmacokinetics , Osteoarthritis/drug therapy , Animals , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Humans , Hydantoins/chemical synthesis , Hydantoins/chemistry , Male , Molecular Structure , Osmosis/drug effects , Osteoarthritis/metabolism , Rats , Rats, Inbred Lew , Structure-Activity Relationship
14.
Org Lett ; 5(11): 1871-4, 2003 May 29.
Article in English | MEDLINE | ID: mdl-12762674

ABSTRACT

[reaction: see text] A series of 2-bromo- and 2-iodo-galactopyranosyl acetates and trichloroacetimidates were evaluated as glycosyl donors for the synthesis of 2-deoxygalactopyranosides. The best selectivity for the beta-glycosidic linkage was achieved by using 6-deoxy-3,4-carbonate-protected galactosyl donors.


Subject(s)
Galactosides/chemical synthesis , Carbohydrate Conformation , Carbohydrate Sequence , Glycosylation , Indicators and Reagents , Oligosaccharides/chemical synthesis , Oligosaccharides/chemistry , Stereoisomerism
15.
Org Lett ; 5(11): 1875-8, 2003 May 29.
Article in English | MEDLINE | ID: mdl-12762675

ABSTRACT

[structure: see text] Highly stereoselective syntheses of functionalized precursors of the CDEF and CDE 2,6-dideoxy-tetra- and trisaccharide units of the anti-HIV aureolic acids durhamycins A and B using 2-deoxy-2-iodo- and 2-deoxy-2-bromopyranosyl donors are described.


Subject(s)
Plicamycin/chemical synthesis , Trisaccharides/chemical synthesis , Carbohydrate Sequence , Glycosides/chemical synthesis , Gram-Positive Bacteria/chemistry , Indicators and Reagents , Molecular Sequence Data , Plicamycin/analogs & derivatives , Plicamycin/chemistry , Stereoisomerism
16.
Org Lett ; 4(1): 135-8, 2002 Jan 10.
Article in English | MEDLINE | ID: mdl-11772109

ABSTRACT

[reaction: see text] Methodology for the conversion of glucuronic acid glycosides to novel bicyclic beta-lactams is reported. Using this strategy, we prepared two novel templates suitable for use in combinatorial chemistry strategies for the construction of a number of interesting beta-lactam motifs. Key features of this strategy include a diastereoselective Ferrier reaction of a glucuronic acid glucal, selective beta-lactam ring formation using a cyclic allylic alcohol, and a chemoselective benzylic oxidation.


Subject(s)
Glucuronic Acid/chemistry , Glycosides/chemistry , beta-Lactams/chemical synthesis , Combinatorial Chemistry Techniques , Indicators and Reagents
17.
J Med Chem ; 57(24): 10476-85, 2014 Dec 26.
Article in English | MEDLINE | ID: mdl-25415648

ABSTRACT

A disintegrin and metalloproteinase with thrombospondin motifs-4 (ADAMTS-4) and ADAMTS-5 are zinc metalloproteases commonly referred to as aggrecanase-1 and aggrecanase-2, respectively. These enzymes are involved in the degradation of aggrecan, a key component of cartilage. Inhibitors of these enzymes could be potential osteoarthritis (OA) therapies. A series of hydantoin inhibitors of ADAMTS-4 and ADAMTS-5 were identified from a screening campaign and optimized through structure-based drug design to give hydantoin 13. Hydantoin 13 had excellent selectivity over other zinc metalloproteases such as TACE, MMP2, MMP3, MMP13, and MMP14. The compound also produced efficacy in both a chemically induced and surgical model of OA in rats.


Subject(s)
ADAM Proteins/antagonists & inhibitors , Benzofurans/pharmacology , Hydantoins/pharmacology , Osteoarthritis/drug therapy , Procollagen N-Endopeptidase/antagonists & inhibitors , Protease Inhibitors/pharmacology , ADAMTS4 Protein , ADAMTS5 Protein , Animals , Benzofurans/chemistry , Cells, Cultured , Crystallography, X-Ray , Hydantoins/chemistry , Male , Menisci, Tibial/drug effects , Menisci, Tibial/pathology , Microsomes/drug effects , Microsomes/metabolism , Models, Anatomic , Models, Molecular , Molecular Structure , Osteoarthritis/pathology , Protease Inhibitors/chemistry , Rats , Rats, Inbred Lew , Structure-Activity Relationship , Tibial Meniscus Injuries
18.
J Org Chem ; 68(1): 27-34, 2003 Jan 10.
Article in English | MEDLINE | ID: mdl-12515457

ABSTRACT

A novel synthetic sequence has been developed to convert simple beta-keto esters into enantiomerically enriched alpha-amino acids. The key features of this sequence include the addition of azide to the C3 position of beta-keto ester derived N-tosyloxy-beta-lactams through a concomitant nucleophilic addition/N-O bond reduction reaction, a mild CsF-induced N1 benzylation of alpha-azido monocyclic beta-lactams, the preparation of alpha-keto-beta-lactams through a novel four-step sequence from the corresponding 3-azido-1-benzyl-beta-lactams, and TEMPO-mediated ring expansion of these compounds to the corresponding N-carboxy anhydrides (NCAs). In addition, the synthesis, isolation, and characterization of unusual 3-imino and 3-chloramino-beta-lactams is reported.


Subject(s)
Amino Acids/chemical synthesis , Azetines/chemistry , Tosyl Compounds/chemistry , beta-Lactams/chemistry , Catalysis , Combinatorial Chemistry Techniques , Esters/chemistry , Molecular Structure , Stereoisomerism
19.
J Org Chem ; 68(1): 35-42, 2003 Jan 10.
Article in English | MEDLINE | ID: mdl-12515458

ABSTRACT

Methodology for the enantioselective synthesis of differentially protected erythro-alpha,beta-diamino acids from N-tosyloxy beta-lactams is reported. The requisite N-tosyloxy beta-lactams are readily available from simple beta-keto esters. The reported approach is flexible and compatible with a variety of functional groups. The synthetic utility of the method is demonstrated through its application to the preparation of an analogue of the antifungal cyclic peptide rhodopeptin B5.


Subject(s)
Amino Acids/chemical synthesis , Antifungal Agents/chemical synthesis , Combinatorial Chemistry Techniques , Peptides, Cyclic/chemical synthesis , beta-Lactams/chemical synthesis , Magnetic Resonance Spectroscopy , Molecular Structure , Stereoisomerism
20.
J Am Chem Soc ; 126(30): 9307-17, 2004 Aug 04.
Article in English | MEDLINE | ID: mdl-15281821

ABSTRACT

The enantioselective total synthesis of the cytotoxic plecomacrolide natural product formamicin (1) is described. Key aspects of this synthesis include the efficient transacetalation reactions of MOM ethers 28 and 38 to form the seven-membered formyl acetals 29 and 39, a late-stage Suzuki cross-coupling reaction of the highly functionalized vinyl boronic acid 6 and vinyl iodide 7, a highly beta-selective glycosidation reaction of beta-hydroxy ketone 4 with 2,6-dideoxy-2-iodoglucopyranosyl fluoride 3, and the global desilylation of penultimate intermediate 77 mediated by in situ generated Et(3)N.2HF.


Subject(s)
Macrolides/chemical synthesis , Glycosylation , Stereoisomerism
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