ABSTRACT
We describe a stereodefined synthesis of the newly identified non-natural phosphorothioate cyclic dinucleotide (CDN) STING agonist, BMT-390025. The new route avoids the low-yielding racemic approach using P(III)-based reagents, and the stereospecific assembly of the phosphorothioate linkages are forged via the recently invented P(V)-based platform of the so-called PSI (Ψ) reagent system. This P(V) approach allows for the complete control of chirality of the P-based linkages and enabled conclusive evidence of the absolute configuration. The new approach offers robust procedures for preparing the stereodefined CDN in eight steps starting from advanced nucelosides, with late-stage direct drop isolations and telescoped steps enabling an efficient scale-up that proceeded in an overall 15% yield to produce multigram amounts of the CDN.
ABSTRACT
The discovery of a series of substituted diarylether compounds as retinoic acid related orphan receptor γt (RORγt) agonists is described. Compound 1 was identified from deck mining as a RORγt agonist. Hit-to-lead optimization led to the identification of lead compound 5, which possesses improved potency (10x). Extensive SAR exploration led to the identification of a potent and selective compound 22, that demonstrated an improved pharmacokinetic profile and a dose-dependent pharmacodynamic response. However, when dosed in a MC38 syngeneic tumor model, no evidence of efficacy was observed. ©2020 Elsevier Science Ltd. All rights reserved.
Subject(s)
Ethers/pharmacology , Nuclear Receptor Subfamily 1, Group F, Member 3/agonists , Tretinoin/pharmacology , Animals , Crystallography, X-Ray , Dose-Response Relationship, Drug , Ethers/chemical synthesis , Ethers/chemistry , Humans , Mice , Models, Molecular , Molecular Structure , Structure-Activity Relationship , Th17 Cells , Tretinoin/chemical synthesis , Tretinoin/chemistryABSTRACT
Substituted benzyloxy aryl compound 2 was identified as an RORγt agonist. Structure based drug design efforts resulted in a potent and selective tricyclic compound 19 which, when administered orally in an MC38 mouse tumor model, demonstrated a desired pharmacokinetic profile as well as a dose-dependent pharmacodynamic response. However, no perceptible efficacy was observed in this tumor model at the doses investigated.
Subject(s)
Benzyl Compounds/pharmacology , Heterocyclic Compounds/pharmacology , Receptors, Retinoic Acid/agonists , Animals , Benzyl Compounds/chemistry , Dose-Response Relationship, Drug , Female , Heterocyclic Compounds/chemistry , Mice , Mice, Inbred C57BL , Molecular Structure , Structure-Activity Relationship , Retinoic Acid Receptor gammaABSTRACT
Lead optimization of the diphenylpyridylethanamine (DPPE) and triphenylethanamine (TPE) series of CETP inhibitors to improve their pharmaceutical profile is described. Polar groups at the N-terminus position in the DPPE series resulted in further improvement in potency and pharmaceutical properties concomitant with retaining the safety, efficacy, and pharmacokinetic (PK) profile. A structure-activity relationship observed in the DPPE series was extended to the corresponding analogs in the more potent TPE series, and further optimization resulted in the identification of 2-amino-N-((R)-1-(3-cyclopropoxy-4-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-4,4,4-trifluoro-3-hydroxy-3-(trifluoromethyl)butanamide (13). Compound 13 demonstrated no significant changes in either mean arterial blood pressure or heart rate in telemetry rats, had an excellent PK profile, and demonstrated robust efficacy in human CETP/apo-B-100 dual transgenic mice and in hamsters.
ABSTRACT
The TGFß-TGFßR signaling pathway has been reported to play a protective role in the later stages of tumorigenesis via increasing immunosuppressive Treg cells and facilitating the epithelial to mesenchymal transition (EMT). Therefore, inhibition of TGFßR has the potential to enhance antitumor immunity. Herein we disclose the identification and optimization of novel heterobicyclic inhibitors of TGFßRI that demonstrate potent inhibition of SMAD phosphorylation. Application of structure-based drug design to the novel pyrrolotriazine chemotype resulted in improved binding affinity (Ki apparentâ¯=â¯0.14â¯nM), long residence time (T1/2â¯>â¯120â¯min) and significantly improved potency in the PSMAD cellular assay (IC50â¯=â¯24â¯nM). Several analogs inhibited phosphorylation of SMAD both in vitro and in vivo. Additionally, inhibition of TGFß-stimulated phospho-SMAD was observed in primary human T cells.
Subject(s)
Bridged Bicyclo Compounds/chemistry , Protein Serine-Threonine Kinases/antagonists & inhibitors , Receptors, Transforming Growth Factor beta/antagonists & inhibitors , Binding Sites , Bridged Bicyclo Compounds/chemical synthesis , Bridged Bicyclo Compounds/pharmacology , Cells, Cultured , Crystallography, X-Ray , Drug Design , Epithelial-Mesenchymal Transition/drug effects , Humans , Molecular Dynamics Simulation , Phosphorylation , Protein Binding , Protein Serine-Threonine Kinases/metabolism , Protein Structure, Tertiary , Pyrroles/chemical synthesis , Pyrroles/chemistry , Pyrroles/metabolism , Receptor, Transforming Growth Factor-beta Type I , Receptors, Transforming Growth Factor beta/metabolism , Smad Proteins/metabolism , Structure-Activity Relationship , T-Lymphocytes/cytology , T-Lymphocytes/metabolism , Thiazines/chemical synthesis , Thiazines/chemistry , Thiazines/metabolismABSTRACT
Cholesteryl ester transfer protein (CETP) inhibitors raise HDL-C in animals and humans and may be antiatherosclerotic by enhancing reverse cholesterol transport (RCT). In this article, we describe the lead optimization efforts resulting in the discovery of a series of triphenylethanamine (TPE) ureas and amides as potent and orally available CETP inhibitors. Compound 10g is a potent CETP inhibitor that maximally inhibited cholesteryl ester (CE) transfer activity at an oral dose of 1 mg/kg in human CETP/apoB-100 dual transgenic mice and increased HDL cholesterol content and size comparable to torcetrapib (1) in moderately-fat fed hamsters. In contrast to the off-target liabilities with 1, no blood pressure increase was observed with 10g in rat telemetry studies and no increase of aldosterone synthase (CYP11B2) was detected in H295R cells. On the basis of its preclinical profile, compound 10g was advanced into preclinical safety studies.
Subject(s)
Anticholesteremic Agents/chemical synthesis , Anticholesteremic Agents/pharmacology , Benzamides/chemical synthesis , Benzamides/pharmacology , Benzylamines/chemical synthesis , Benzylamines/pharmacology , Cholesterol Ester Transfer Proteins/antagonists & inhibitors , Animals , Anticholesteremic Agents/pharmacokinetics , Atherosclerosis/drug therapy , Benzamides/pharmacokinetics , Benzylamines/pharmacokinetics , Blood Pressure/drug effects , Cell Line , Cholesterol/metabolism , Cholesterol, HDL/blood , Cricetinae , Cytochrome P-450 CYP11B2/antagonists & inhibitors , Dogs , Drug Discovery , Humans , Macaca fascicularis , Male , Mesocricetus , Mice , Mice, Transgenic , Motor Activity/drug effects , Quinolines/pharmacology , Rats , Rats, Sprague-DawleyABSTRACT
A series of diphenylpyridylethanamine-based inhibitors of cholesteryl ester transfer protein with aminoheterocycles appended onto the N-terminus of the chemotype were explored as urea mimetics. Potent compounds were discovered and were further optimized to improve metabolic stability and PXR transactivation profile.
Subject(s)
Cholesterol Ester Transfer Proteins/antagonists & inhibitors , Heterocyclic Compounds/chemical synthesis , Heterocyclic Compounds/pharmacology , Biomimetics , Biphenyl Compounds/chemical synthesis , Biphenyl Compounds/chemistry , Biphenyl Compounds/pharmacology , Drug Stability , Ethylamines/chemical synthesis , Ethylamines/chemistry , Ethylamines/pharmacology , Heterocyclic Compounds/chemistry , Humans , Inhibitory Concentration 50 , Molecular Structure , Pyridines/chemical synthesis , Pyridines/chemistry , Pyridines/pharmacology , Structure-Activity Relationship , Urea/chemistryABSTRACT
A series of diphenylpyridylethanamine (DPPE) derivatives was identified exhibiting potent CETP inhibition. Replacing the labile ester functionality in the initial lead 7 generated a series of amides and ureas. Further optimization of the DPPE series for potency resulted in the discovery of cyclopentylurea 15d, which demonstrated a reduction in cholesterol ester transfer activity (48% of predose level) in hCETP/apoB-100 dual transgenic mice. The PK profile of 15d was suboptimal, and further optimization of the N-terminus resulted in the discovery of amide 20 with an improved PK profile and robust efficacy in transgenic hCETP/apoB-100 mice and in hamsters. Compound 20 demonstrated no significant changes in either mean arterial blood pressure or heart rate in telemeterized rats despite sustained high exposures.
Subject(s)
Anticholesteremic Agents/chemistry , Anticholesteremic Agents/pharmacology , Cholesterol Ester Transfer Proteins/antagonists & inhibitors , Pyridines/chemistry , Pyridines/pharmacology , Stilbenes/chemistry , Stilbenes/pharmacology , Animals , Anticholesteremic Agents/chemical synthesis , Apolipoprotein B-100/antagonists & inhibitors , Apolipoprotein B-100/metabolism , Blood Pressure/drug effects , Cholesterol Ester Transfer Proteins/metabolism , Coronary Disease/drug therapy , Cricetinae , Drug Discovery , Heart Rate/drug effects , Humans , Inhibitory Concentration 50 , Male , Mice , Mice, Transgenic , Molecular Structure , Pyridines/chemical synthesis , Rats , Stilbenes/chemical synthesisABSTRACT
Identification, synthesis and structure-activity relationship of small-molecule VIPR1 antagonists encompassing two chemical series are described.
Subject(s)
Antineoplastic Agents/chemical synthesis , Biphenyl Compounds/chemical synthesis , Receptors, Vasoactive Intestinal Polypeptide, Type I/antagonists & inhibitors , Thiophenes/chemical synthesis , Antineoplastic Agents/pharmacology , Biphenyl Compounds/pharmacology , Cell Line, Tumor , Drug Screening Assays, Antitumor , High-Throughput Screening Assays , Humans , Receptors, Vasoactive Intestinal Polypeptide, Type I/metabolism , Small Molecule Libraries , Structure-Activity Relationship , Thiophenes/pharmacologyABSTRACT
SAR studies of pyrrolo[1,2-f]triazines as JAK2 inhibitors is presented. Achieving JAK2 inhibition selectively over JAK3 is discussed.
Subject(s)
Enzyme Activation/drug effects , Enzyme Inhibitors/pharmacology , Janus Kinase 2/metabolism , Janus Kinase 3/metabolism , Pyrrolidines/chemical synthesis , Triazines/chemical synthesis , Triazines/pharmacology , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Janus Kinase 2/antagonists & inhibitors , Models, Molecular , Molecular Structure , Protein Binding , Pyrroles/chemical synthesis , Pyrroles/chemistry , Pyrroles/pharmacology , Pyrrolidines/chemistry , Pyrrolidines/pharmacology , Structure-Activity Relationship , Triazines/chemistryABSTRACT
A G-Protein-coupled receptor-targeted library of aryloxypropanolamines and aryloxybutanolamines was efficiently executed using a novel, polymer-supported acyclic acetal linker, producing compounds in good yields and purities.
Subject(s)
Amines/chemical synthesis , Drug Design , Receptors, G-Protein-Coupled/antagonists & inhibitors , Small Molecule Libraries/chemical synthesis , Amines/pharmacology , Combinatorial Chemistry Techniques , Cross-Linking Reagents , Humans , Polymers , Propanolamines , Small Molecule Libraries/pharmacologyABSTRACT
2-Arylbenzoxazole 5 was identified as a hit from a fluorescence-based high-throughput screen for CETP inhibitors. The synthesis and SAR investigation employing array synthesis of the A- and B-rings are described.
