Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 70
Filter
Add more filters










Publication year range
1.
J Med Chem ; 66(23): 15750-15760, 2023 12 14.
Article in English | MEDLINE | ID: mdl-38009718

ABSTRACT

CaMKK2 signals through AMPK-dependent and AMPK-independent pathways to trigger cellular outputs including proliferation, differentiation, and migration, resulting in changes to metabolism, bone mass accrual, neuronal function, hematopoiesis, and immunity. CAMKK2 is upregulated in tumors including hepatocellular carcinoma, prostate, breast, and gastric cancer, and genetic deletion in myeloid cells results in increased antitumor immunity in several syngeneic models. Validation of the biological roles of CaMKK2 has relied on genetic deletion or small molecule inhibitors with activity against several biological targets. We sought to generate selective inhibitors and degraders to understand the biological impact of inhibiting catalytic activity and scaffolding and the potential therapeutic benefits of targeting CaMKK2. We report herein selective, ligand-efficient inhibitors and ligand-directed degraders of CaMKK2 that were used to probe immune and tumor intrinsic biology. These molecules provide two distinct strategies for ablating CaMKK2 signaling in vitro and in vivo.


Subject(s)
AMP-Activated Protein Kinases , Liver Neoplasms , Male , Humans , AMP-Activated Protein Kinases/metabolism , Calcium , Calcium-Calmodulin-Dependent Protein Kinase Kinase , Ligands
2.
J Med Chem ; 66(13): 9095-9119, 2023 07 13.
Article in English | MEDLINE | ID: mdl-37399505

ABSTRACT

The allosteric inhibitor of the mechanistic target of rapamycin (mTOR) everolimus reduces seizures in tuberous sclerosis complex (TSC) patients through partial inhibition of mTOR functions. Due to its limited brain permeability, we sought to develop a catalytic mTOR inhibitor optimized for central nervous system (CNS) indications. We recently reported an mTOR inhibitor (1) that is able to block mTOR functions in the mouse brain and extend the survival of mice with neuronal-specific ablation of the Tsc1 gene. However, 1 showed the risk of genotoxicity in vitro. Through structure-activity relationship (SAR) optimization, we identified compounds 9 and 11 without genotoxicity risk. In neuronal cell-based models of mTOR hyperactivity, both corrected aberrant mTOR activity and significantly improved the survival rate of mice in the Tsc1 gene knockout model. Unfortunately, 9 and 11 showed limited oral exposures in higher species and dose-limiting toxicities in cynomolgus macaque, respectively. However, they remain optimal tools to explore mTOR hyperactivity in CNS disease models.


Subject(s)
MTOR Inhibitors , Sirolimus , Mice , Animals , Syndrome , Central Nervous System/metabolism , Brain/metabolism , TOR Serine-Threonine Kinases , Adenosine Triphosphate
3.
Biochem Pharmacol ; 209: 115418, 2023 03.
Article in English | MEDLINE | ID: mdl-36693437

ABSTRACT

Myeloperoxidase (MPO) is a heme-containing peroxidase from phagocytic cells, which plays an important role in the innate immune response. The primary anti-microbial function of MPO is achieved by catalyzing the oxidation of halides by hydrogen peroxide (H2O2). Upon activation of phagocytes, MPO activity is detectable in both phagosomes and extracellularly, where it can remain or transcytose into interstitial compartments. Activated MPO leads to oxidative stress and tissue damage in many inflammatory states, including cardiovascular disease. Starting from a low molecular weight (LMW) high throughput screening (HTS) hit, here we report the discovery of a novel pyrrolidinone indole (IN-4) as a highly potent MPO inhibitor. This compound displays similar in vitro potency across peroxidation, plasma and NETosis assays. In a dilution/dialysis study, <5% of the original MPO activity was detected post-incubation of MPO with IN-4, suggesting irreversible enzyme inhibition. A fast MPO inactivation rate (kinact/Ki) and low partition ratio (k3/k4) make IN-4 kinetic properties attractive for an MPO inhibitor. This compound also displays significant selectivity over the closely related thyroid peroxidase (TPO), and is selective for extracellular MPO over intracellular (neutrophil) MPO. Moreover, IN-4 shows good exposure, low clearance and high oral bioavailability in mice, rats and dogs. The high in vitro MPO activity and high oral exposure observed with IN-4 result in a dose-dependent inhibition of MPO activity in three mouse models of inflammation. In conclusion, IN-4 is a novel, potent, mechanism-based and selective MPO inhibitor, which may be used as superior therapeutic agent to treat multiple inflammatory conditions, including cardiovascular disease.


Subject(s)
Cardiovascular Diseases , Peroxidase , Rats , Mice , Animals , Dogs , Hydrogen Peroxide , Antioxidants , Indoles , Pyrrolidinones
4.
PLoS One ; 16(11): e0248034, 2021.
Article in English | MEDLINE | ID: mdl-34752458

ABSTRACT

Retinoic acid receptor-related orphan nuclear receptor (ROR) γt is a member of the RORC nuclear hormone receptor family of transcription factors. RORγt functions as a critical regulator of thymopoiesis and immune responses. RORγt is expressed in multiple immune cell populations including Th17 cells, where its primary function is regulation of immune responses to bacteria and fungi through IL-17A production. However, excessive IL-17A production has been linked to numerous autoimmune diseases. Moreover, Th17 cells have been shown to elicit both pro- and anti-tumor effects. Thus, modulation of the RORγt/IL-17A axis may represent an attractive therapeutic target for the treatment of autoimmune disorders and some cancers. Herein we report the design, synthesis and characterization of three selective allosteric RORγt inhibitors in preclinical models of inflammation and tumor growth. We demonstrate that these compounds can inhibit Th17 differentiation and maintenance in vitro and Th17-dependent inflammation and associated gene expression in vivo, in a dose-dependent manner. Finally, RORγt inhibitors were assessed for efficacy against tumor formation. While, RORγt inhibitors were shown to inhibit tumor formation in pancreatic ductal adenocarcinoma (PDAC) organoids in vitro and modulate RORγt target genes in vivo, this activity was not sufficient to delay tumor volume in a KP/C human tumor mouse model of pancreatic cancer.


Subject(s)
Gene Expression/drug effects , Inflammation/genetics , Nuclear Receptor Subfamily 1, Group F, Member 1/antagonists & inhibitors , Th17 Cells/drug effects , Animals , Carcinogenesis/drug effects , Carcinogenesis/genetics , Inflammation/metabolism , Interleukin-17/metabolism , Mice , Nuclear Receptor Subfamily 1, Group F, Member 1/metabolism , Signal Transduction/drug effects , Signal Transduction/genetics , Th17 Cells/metabolism
5.
ChemMedChem ; 16(15): 2417-2423, 2021 08 05.
Article in English | MEDLINE | ID: mdl-34114371

ABSTRACT

The second biannual Alpine Winter Conference on Medicinal and Synthetic Chemistry (short: Alpine Winter Conference) took place January 19-23, 2020, in St. Anton in western Austria. There were roughly 180 attendees from around the globe, making this mid-sized conference particularly conducive to networking and exchanging ideas over the course of four and a half days. This report summarizes the key events and presentations given by researchers working in both industry and academia.


Subject(s)
Chemistry, Pharmaceutical , Research Personnel , Austria , Humans
6.
J Med Chem ; 64(8): 4744-4761, 2021 04 22.
Article in English | MEDLINE | ID: mdl-33822618

ABSTRACT

Spinal muscular atrophy (SMA) is a debilitating neuromuscular disease caused by low levels of functional survival motor neuron protein (SMN) resulting from a deletion or loss of function mutation of the survival motor neuron 1 (SMN1) gene. Branaplam (1) elevates levels of full-length SMN protein in vivo by modulating the splicing of the related gene SMN2 to enhance the exon-7 inclusion and increase levels of the SMN. The intramolecular hydrogen bond present in the 2-hydroxyphenyl pyridazine core of 1 enforces a planar conformation of the biaryl system and is critical for the compound activity. Scaffold morphing revealed that the pyridazine could be replaced by a 1,3,4-thiadiazole, which provided additional opportunities for a conformational constraint of the biaryl through intramolecular 1,5-sulfur-oxygen (S···O) or 1,5-sulfur-halogen (S···X) noncovalent interactions. Compound 26, which incorporates a 2-fluorophenyl thiadiazole motif, demonstrated a greater than 50% increase in production of full-length SMN protein in a mouse model of SMA.


Subject(s)
Drug Design , RNA Splicing , Thiadiazoles/chemistry , Animals , Half-Life , Halogens/chemistry , Humans , Male , Mice , Molecular Conformation , Motor Neurons/metabolism , Muscular Atrophy, Spinal/genetics , Muscular Atrophy, Spinal/pathology , Oxygen/chemistry , Pyridazines/chemistry , RNA Splicing/drug effects , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Sulfur/chemistry , Survival of Motor Neuron 1 Protein/genetics , Survival of Motor Neuron 1 Protein/metabolism , Survival of Motor Neuron 2 Protein/genetics , Survival of Motor Neuron 2 Protein/metabolism , Thiadiazoles/metabolism , Thiadiazoles/pharmacology
7.
J Am Chem Soc ; 143(10): 4055-4063, 2021 03 17.
Article in English | MEDLINE | ID: mdl-33666086

ABSTRACT

This paper describes an intermolecular cross-selective [2 + 2] photocycloaddition reaction of exocyclic arylidene oxetanes, azetidines, and cyclobutanes with simple electron-deficient alkenes. The reaction takes place under mild conditions using a commercially available Ir(III) photosensitizer upon blue light irradiation. This transformation provides access to a range of polysubstituted 2-oxaspiro[3.3]heptane, 2-azaspiro[3.3]heptane, and spiro[3.3]heptane motifs, which are of prime interest in medicinal chemistry as gem-dimethyl and carbonyl bioisosteres. A variety of further transformations of the initial cycloadducts are demonstrated to highlight the versatility of the products and enable selective access to either of a syn- or an anti-diastereoisomer through kinetic or thermodynamic epimerization, respectively. Mechanistic experiments and DFT calculations suggest that this reaction proceeds through a sensitized energy transfer pathway.

8.
J Am Chem Soc ; 143(1): 97-102, 2021 01 13.
Article in English | MEDLINE | ID: mdl-33369395

ABSTRACT

Intermolecular C-C bond-forming reactions are underdeveloped transformations in the field of biocatalysis. Here we report a photoenzymatic intermolecular hydroalkylation of olefins catalyzed by flavin-dependent 'ene'-reductases. Radical initiation occurs via photoexcitation of a rare high-order enzyme-templated charge-transfer complex that forms between an alkene, α-chloroamide, and flavin hydroquinone. This unique mechanism ensures that radical formation only occurs when both substrates are present within the protein active site. This active site can control the radical terminating hydrogen atom transfer, enabling the synthesis of enantioenriched γ-stereogenic amides. This work highlights the potential for photoenzymatic catalysis to enable new biocatalytic transformations via previously unknown electron transfer mechanisms.


Subject(s)
Alkenes/chemistry , Amides/chemical synthesis , Flavoproteins/chemistry , Oxidoreductases/chemistry , Alkylation/radiation effects , Biocatalysis/radiation effects , Catalytic Domain , Dinitrocresols/chemistry , Dinitrocresols/radiation effects , Flavoproteins/radiation effects , Light , Models, Chemical , Oxidoreductases/radiation effects
9.
Bioorg Med Chem ; 28(12): 115548, 2020 06 15.
Article in English | MEDLINE | ID: mdl-32503688

ABSTRACT

Myeloperoxidase (MPO) activity and subsequent generation of hypochlorous acid has been associated with the killing of host-invading microorganisms (e.g. bacteria, viruses, and fungi). However, during oxidative stress, high MPO activity can damage host tissue and is linked to several chronic inflammatory conditions. Herein, we describe the development of a novel biaryl, indole-pyrazole series of irreversible mechanism-based inhibitors of MPO. Derived from an indole-containing high-throughput screen hit, optimization efforts resulted in potent and selective 6-substituted indoles with good oral bioavailability and in vivo activity.


Subject(s)
Enzyme Inhibitors/metabolism , Indoles/metabolism , Peroxidase/metabolism , Animals , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/therapeutic use , Half-Life , Indoles/chemistry , Indoles/pharmacokinetics , Indoles/therapeutic use , Mice , Peritonitis/drug therapy , Peritonitis/pathology , Peroxidase/antagonists & inhibitors , Pyrazoles/chemistry , Pyrazoles/metabolism , Pyrazoles/pharmacokinetics , Structure-Activity Relationship
10.
Nat Struct Mol Biol ; 27(4): 319-322, 2020 04.
Article in English | MEDLINE | ID: mdl-32251415

ABSTRACT

Thalidomide-dependent degradation of the embryonic transcription factor SALL4 by the CRL4CRBN E3 ubiquitin ligase is a plausible major driver of thalidomide teratogenicity. The structure of the second zinc finger of SALL4 in complex with pomalidomide, cereblon and DDB1 reveals the molecular details of recruitment. Sequence differences and a shifted binding position relative to Ikaros offer a path to the rational design of cereblon-binding drugs with reduced teratogenic risk.


Subject(s)
Adaptor Proteins, Signal Transducing/chemistry , DNA-Binding Proteins/ultrastructure , Multiprotein Complexes/ultrastructure , Transcription Factors/ultrastructure , Adaptor Proteins, Signal Transducing/genetics , Crystallography, X-Ray , DNA-Binding Proteins/chemistry , DNA-Binding Proteins/genetics , Humans , Multiprotein Complexes/chemistry , Multiprotein Complexes/genetics , Protein Binding , Protein Conformation , Proteolysis/drug effects , Substrate Specificity , Thalidomide/analogs & derivatives , Thalidomide/chemistry , Thalidomide/pharmacology , Transcription Factors/chemistry , Transcription Factors/genetics , Ubiquitin-Protein Ligases/chemistry , Ubiquitin-Protein Ligases/ultrastructure , Ubiquitination/genetics
11.
J Med Chem ; 63(13): 6648-6676, 2020 07 09.
Article in English | MEDLINE | ID: mdl-32130004

ABSTRACT

Many patients with multiple myeloma (MM) initially respond to treatment with modern combination regimens including immunomodulatory agents (lenalidomide and pomalidomide) and proteasome inhibitors. However, some patients lack an initial response to therapy (i.e., are refractory), and although the mean survival of MM patients has more than doubled in recent years, most patients will eventually relapse. To address this need, we explored the potential of novel cereblon E3 ligase modulators (CELMoDs) for the treatment of patients with relapsed or refractory multiple myeloma (RRMM). We found that optimization beyond potency of degradation, including degradation efficiency and kinetics, could provide efficacy in a lenalidomide-resistant setting. Guided by both phenotypic and protein degradation data, we describe a series of CELMoDs for the treatment of RRMM, culminating in the discovery of CC-92480, a novel protein degrader and the first CELMoD to enter clinical development that was specifically designed for efficient and rapid protein degradation kinetics.


Subject(s)
Adaptor Proteins, Signal Transducing/metabolism , Antineoplastic Agents/pharmacology , Multiple Myeloma/drug therapy , Ubiquitin-Protein Ligases/metabolism , Adaptor Proteins, Signal Transducing/antagonists & inhibitors , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/therapeutic use , Cell Line, Tumor , Cell Proliferation/drug effects , Female , Humans , Inhibitory Concentration 50 , Mice , Multiple Myeloma/pathology , Recurrence , Stereoisomerism , Treatment Failure , Ubiquitin-Protein Ligases/antagonists & inhibitors , Xenograft Model Antitumor Assays
12.
J Med Chem ; 63(3): 1068-1083, 2020 02 13.
Article in English | MEDLINE | ID: mdl-31955578

ABSTRACT

Recent clinical evaluation of everolimus for seizure reduction in patients with tuberous sclerosis complex (TSC), a disease with overactivated mechanistic target of rapamycin (mTOR) signaling, has demonstrated the therapeutic value of mTOR inhibitors for central nervous system (CNS) indications. Given that everolimus is an incomplete inhibitor of the mTOR function, we sought to develop a new mTOR inhibitor that has improved properties and is suitable for CNS disorders. Starting from an in-house purine-based compound, optimization of the physicochemical properties of a thiazolopyrimidine series led to the discovery of the small molecule 7, a potent and selective brain-penetrant ATP-competitive mTOR inhibitor. In neuronal cell-based models of mTOR hyperactivity, 7 corrected the mTOR pathway activity and the resulting neuronal overgrowth phenotype. The new mTOR inhibitor 7 showed good brain exposure and significantly improved the survival rate of mice with neuronal-specific ablation of the Tsc1 gene. These results demonstrate the potential utility of this tool compound to test therapeutic hypotheses that depend on mTOR hyperactivity in the CNS.


Subject(s)
Protein Kinase Inhibitors/therapeutic use , Pyrimidines/therapeutic use , Seizures/drug therapy , TOR Serine-Threonine Kinases/antagonists & inhibitors , Thiazoles/therapeutic use , Animals , Anticonvulsants/metabolism , Anticonvulsants/pharmacokinetics , Anticonvulsants/therapeutic use , Binding Sites , Brain/drug effects , Drug Discovery , Humans , Male , Mice, Inbred C57BL , Mice, Knockout , Neurons/drug effects , Protein Binding , Protein Kinase Inhibitors/metabolism , Protein Kinase Inhibitors/pharmacokinetics , Pyrimidines/metabolism , Pyrimidines/pharmacokinetics , Rats , TOR Serine-Threonine Kinases/chemistry , TOR Serine-Threonine Kinases/metabolism , Thiazoles/metabolism , Thiazoles/pharmacokinetics , Tuberous Sclerosis Complex 1 Protein/genetics
13.
ACS Med Chem Lett ; 10(12): 1592-1602, 2019 Dec 12.
Article in English | MEDLINE | ID: mdl-31857833

ABSTRACT

Many cellular processes and pathways are mediated by the regulation of protein-protein complexes. For example, E3 ubiquitin ligases recruit substrate proteins and transfer a ubiquitin tag to target those proteins for destruction by the proteasome. It has now been shown that this cellular process for protein destruction can be redirected by small molecules in both laboratory and clinical settings. This presents a new paradigm in drug discovery, enabling the rapid removal of target proteins linked to disease. In this Innovations review, we will describe the work done on cereblon as a case study on the different strategies available for targeted protein degradation.

14.
Nat Chem Biol ; 15(10): 937-944, 2019 10.
Article in English | MEDLINE | ID: mdl-31527835

ABSTRACT

Targeted protein degradation as a therapeutic modality has seen dramatic progress and massive investment in recent years because of the convergence of two key scientific breakthroughs: optimization of first-generation peptidic proteolysis-targeted chimeras (PROTACs) into more drug-like molecules able to support in vivo proof of concept and the discovery that clinical molecules function as degraders by binding and repurposing the proteins cereblon and DCAF15. This provided clinical validation for the general approach through the cereblon modulator class of drugs and provided highly drug-like and ligand-efficient E3 ligase binders upon which to tether target-binding moieties. Increasingly rational and systematic approaches including biophysical and structural studies on ternary complexes are being leveraged as the field advances. In this Perspective we summarize the discoveries that have laid the foundation for future degradation therapeutics, focusing on those classes of small molecules that redirect E3 ubiquitin ligases to non-native substrates.


Subject(s)
Proteolysis/drug effects , Binding Sites , Humans , Proteasome Endopeptidase Complex , Protein Binding , Small Molecule Libraries/chemistry , Ubiquitin-Protein Ligases/chemistry , Ubiquitin-Protein Ligases/metabolism
15.
Chem Sci ; 10(41): 9591-9596, 2019 Nov 07.
Article in English | MEDLINE | ID: mdl-32064071

ABSTRACT

A large proportion of medicinally relevant molecules bear nitrogen and sp3-hybridized carbon functionalities. Overwhelmingly, these atoms are found as part of (hetero)cyclic structures. Despite their importance, synthetic approaches to saturated nitrogen heterocycles are limited to several established stoichiometric alkylation techniques, as well as a few methods involving C-H bond activation. The synthetic community remains interested in more general, mild, and sustainable ways to access these motifs. Here we describe a dual-catalyst system composed of an iridium photocatalyst and a lithium phosphate base that is capable of selectively homolyzing the N-H bond of 4-alkyl-1,4-dihydropyridines, presumably by proton-coupled-electron-transfer (PCET), and mediating efficient cyclization of the resultant carbon-centered radicals with tethered imines. The outcome of this transformation is access to a broad range of structurally complex nitrogen heterocycles obtainable from simple aldehyde starting materials in a highly chemoselective manner.

16.
J Med Chem ; 61(24): 11021-11036, 2018 12 27.
Article in English | MEDLINE | ID: mdl-30407821

ABSTRACT

Spinal muscular atrophy (SMA), a rare neuromuscular disorder, is the leading genetic cause of death in infants and toddlers. SMA is caused by the deletion or a loss of function mutation of the survival motor neuron 1 (SMN1) gene. In humans, a second closely related gene SMN2 exists; however it codes for a less stable SMN protein. In recent years, significant progress has been made toward disease modifying treatments for SMA by modulating SMN2 pre-mRNA splicing. Herein, we describe the discovery of LMI070/branaplam, a small molecule that stabilizes the interaction between the spliceosome and SMN2 pre-mRNA. Branaplam (1) originated from a high-throughput phenotypic screening hit, pyridazine 2, and evolved via multiparameter lead optimization. In a severe mouse SMA model, branaplam treatment increased full-length SMN RNA and protein levels, and extended survival. Currently, branaplam is in clinical studies for SMA.


Subject(s)
Brain/drug effects , ERG1 Potassium Channel/metabolism , Muscular Atrophy, Spinal/drug therapy , Pyridazines/chemistry , Administration, Oral , Animals , Brain/metabolism , Cell Line , Crystallography, X-Ray , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical/methods , ERG1 Potassium Channel/antagonists & inhibitors , Humans , Mice, Inbred C57BL , Motor Neurons/drug effects , Muscular Atrophy, Spinal/genetics , Pyridazines/pharmacology , Quantitative Structure-Activity Relationship , RNA Splicing , Rats, Sprague-Dawley , Survival of Motor Neuron 1 Protein/genetics , Survival of Motor Neuron 1 Protein/metabolism , Survival of Motor Neuron 2 Protein/genetics
17.
Nat Chem Biol ; 14(10): 981-987, 2018 10.
Article in English | MEDLINE | ID: mdl-30190590

ABSTRACT

Targeted protein degradation via small-molecule modulation of cereblon offers vast potential for the development of new therapeutics. Cereblon-binding therapeutics carry the safety risks of thalidomide, which caused an epidemic of severe birth defects characterized by forelimb shortening or phocomelia. Here we show that thalidomide is not teratogenic in transgenic mice expressing human cereblon, indicating that binding to cereblon is not sufficient to cause birth defects. Instead, we identify SALL4 as a thalidomide-dependent cereblon neosubstrate. Human mutations in SALL4 cause Duane-radial ray, IVIC, and acro-renal-ocular syndromes with overlapping clinical presentations to thalidomide embryopathy, including phocomelia. SALL4 is degraded in rabbits but not in resistant organisms such as mice because of SALL4 sequence variations. This work expands the scope of cereblon neosubstrate activity within the formerly 'undruggable' C2H2 zinc finger family and offers a path toward safer therapeutics through an improved understanding of the molecular basis of thalidomide-induced teratogenicity.


Subject(s)
Gene Expression Regulation , Peptide Hydrolases/chemistry , Teratogens/chemistry , Thalidomide/chemistry , Transcription Factors/chemistry , Adaptor Proteins, Signal Transducing , Animals , DNA-Binding Proteins/chemistry , DNA-Binding Proteins/genetics , Homozygote , Humans , Immunohistochemistry , Induced Pluripotent Stem Cells , Ligands , Male , Mice , Mice, Transgenic , Mutation , Nerve Tissue Proteins/chemistry , Nerve Tissue Proteins/genetics , Peptide Hydrolases/genetics , Proteolysis , Rabbits , Testis/metabolism , Transcription Factors/genetics , Ubiquitin-Protein Ligases/metabolism , Zinc Fingers
18.
J Pharmacol Exp Ther ; 367(1): 147-154, 2018 10.
Article in English | MEDLINE | ID: mdl-30076263

ABSTRACT

Myeloperoxidase (MPO) is a leukocyte-derived redox enzyme that has been linked to oxidative stress and damage in many inflammatory states, including cardiovascular disease. We have discovered aminopyridines that are potent mechanism-based inhibitors of MPO, with significant selectivity over the closely related thyroid peroxidase. 1-((6-Aminopyridin-3-yl)methyl)-3-(4-bromophenyl)urea (Aminopyridine 2) inhibited MPO in human plasma and blocked MPO-dependent vasomotor dysfunction ex vivo in rat aortic rings. Aminopyridine 2 also showed high oral bioavailability and inhibited MPO activity in vivo in a mouse model of peritonitis. Aminopyridine 2 could effectively be administered as a food admixture, making it an important tool for assessing the relative importance of MPO in preclinical models of chronic inflammatory disease.


Subject(s)
Aminopyridines/pharmacology , Enzyme Inhibitors/pharmacology , Peroxidase/antagonists & inhibitors , Animals , Aorta/drug effects , Aorta/metabolism , Biological Availability , Humans , Inflammation/drug therapy , Inflammation/metabolism , Male , Mice , Mice, Inbred C57BL , Rats , Rats, Sprague-Dawley
19.
J Med Chem ; 61(7): 2837-2864, 2018 04 12.
Article in English | MEDLINE | ID: mdl-29562737

ABSTRACT

In breast cancer, estrogen receptor alpha (ERα) positive cancer accounts for approximately 74% of all diagnoses, and in these settings, it is a primary driver of cell proliferation. Treatment of ERα positive breast cancer has long relied on endocrine therapies such as selective estrogen receptor modulators, aromatase inhibitors, and selective estrogen receptor degraders (SERDs). The steroid-based anti-estrogen fulvestrant (5), the only approved SERD, is effective in patients who have not previously been treated with endocrine therapy as well as in patients who have progressed after receiving other endocrine therapies. Its efficacy, however, may be limited due to its poor physicochemical properties. We describe the design and synthesis of a series of potent benzothiophene-containing compounds that exhibit oral bioavailability and preclinical activity as SERDs. This article culminates in the identification of LSZ102 (10), a compound in clinical development for the treatment of ERα positive breast cancer.


Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Breast Neoplasms/drug therapy , Breast Neoplasms/metabolism , Estrogen Receptor alpha/drug effects , Selective Estrogen Receptor Modulators/chemical synthesis , Selective Estrogen Receptor Modulators/pharmacology , Thiophenes/chemical synthesis , Thiophenes/pharmacology , Animals , Antineoplastic Agents/pharmacokinetics , Biological Availability , Drug Design , Drug Discovery , Female , Humans , MCF-7 Cells , Mice , Mice, Nude , Rats , Rats, Sprague-Dawley , Rats, Wistar , Selective Estrogen Receptor Modulators/pharmacokinetics , Thiophenes/chemistry , Thiophenes/pharmacokinetics , Xenograft Model Antitumor Assays
20.
J Med Chem ; 60(12): 5002-5014, 2017 06 22.
Article in English | MEDLINE | ID: mdl-28549219

ABSTRACT

Over the past several decades, the frequency of antibacterial resistance in hospitals, including multidrug resistance (MDR) and its association with serious infectious diseases, has increased at alarming rates. Pseudomonas aeruginosa is a leading cause of nosocomial infections, and resistance to virtually all approved antibacterial agents is emerging in this pathogen. To address the need for new agents to treat MDR P. aeruginosa, we focused on inhibiting the first committed step in the biosynthesis of lipid A, the deacetylation of uridyldiphospho-3-O-(R-hydroxydecanoyl)-N-acetylglucosamine by the enzyme LpxC. We approached this through the design, synthesis, and biological evaluation of novel hydroxamic acid LpxC inhibitors, exemplified by 1, where cytotoxicity against mammalian cell lines was reduced, solubility and plasma-protein binding were improved while retaining potent anti-pseudomonal activity in vitro and in vivo.


Subject(s)
Amidohydrolases/antagonists & inhibitors , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Amidohydrolases/chemistry , Animals , Anti-Bacterial Agents/chemical synthesis , Chemistry Techniques, Synthetic , Crystallography, X-Ray , Drug Design , Drug Evaluation, Preclinical/methods , Drug Resistance, Multiple, Bacterial/drug effects , Enzyme Inhibitors/chemical synthesis , Female , Hep G2 Cells/drug effects , Humans , K562 Cells/drug effects , Mice, Inbred BALB C , Microbial Sensitivity Tests , Molecular Docking Simulation , Pseudomonas Infections/drug therapy , Pseudomonas aeruginosa/drug effects , Pseudomonas aeruginosa/enzymology , Structure-Activity Relationship
SELECTION OF CITATIONS
SEARCH DETAIL
...