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1.
Cell ; 178(5): 1222-1230.e10, 2019 08 22.
Article in English | MEDLINE | ID: mdl-31442409

ABSTRACT

The CC chemokine receptor 7 (CCR7) balances immunity and tolerance by homeostatic trafficking of immune cells. In cancer, CCR7-mediated trafficking leads to lymph node metastasis, suggesting the receptor as a promising therapeutic target. Here, we present the crystal structure of human CCR7 fused to the protein Sialidase NanA by using data up to 2.1 Å resolution. The structure shows the ligand Cmp2105 bound to an intracellular allosteric binding pocket. A sulfonamide group, characteristic for various chemokine receptor ligands, binds to a patch of conserved residues in the Gi protein binding region between transmembrane helix 7 and helix 8. We demonstrate how structural data can be used in combination with a compound repository and automated thermal stability screening to identify and modulate allosteric chemokine receptor antagonists. We detect both novel (CS-1 and CS-2) and clinically relevant (CXCR1-CXCR2 phase-II antagonist Navarixin) CCR7 modulators with implications for multi-target strategies against cancer.


Subject(s)
Ligands , Receptors, CCR7/metabolism , Allosteric Regulation , Binding Sites , Crystallography, X-Ray , Humans , Molecular Dynamics Simulation , Neuraminidase/genetics , Neuraminidase/metabolism , Protein Binding , Protein Structure, Tertiary , Receptors, CCR2/chemistry , Receptors, CCR2/metabolism , Receptors, CCR7/antagonists & inhibitors , Receptors, CCR7/genetics , Recombinant Fusion Proteins/biosynthesis , Recombinant Fusion Proteins/chemistry , Recombinant Fusion Proteins/isolation & purification
2.
Bioorg Med Chem Lett ; 29(9): 1074-1078, 2019 05 01.
Article in English | MEDLINE | ID: mdl-30857747

ABSTRACT

A seven-membered cyclic chiral analog of potent lead BTK inhibitor 1 was envisioned by structure-based design to lock the molecule into its bioactive conformation. For the elaboration of the seven-membered ring, compound 1 pyridone 6-position was substituted with the purpose to prevent formation of reactive metabolites. Eventually, the cyclic chiral compound 3 maintained the high potency of 1, and most importantly showed no activity at either GSH or TDI assays suggesting no formation of reactive metabolites. The anticipated bound conformation of 3 to BTK was confirmed by X-ray crystallography. Synthetically, the crucial seven-membered ring formation was obtained by using TosMIC as a connective reagent.


Subject(s)
Agammaglobulinaemia Tyrosine Kinase/antagonists & inhibitors , Drug Design , Protein Kinase Inhibitors/chemistry , Agammaglobulinaemia Tyrosine Kinase/metabolism , Binding Sites , Crystallography, X-Ray , Humans , Molecular Conformation , Molecular Docking Simulation , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/metabolism , Protein Structure, Tertiary , Stereoisomerism , Structure-Activity Relationship
3.
J Comput Aided Mol Des ; 33(3): 307-330, 2019 03.
Article in English | MEDLINE | ID: mdl-30756207

ABSTRACT

Targeting the interaction with or displacement of the 'right' water molecule can significantly increase inhibitor potency in structure-guided drug design. Multiple computational approaches exist to predict which waters should be targeted for displacement to achieve the largest gain in potency. However, the relative success of different methods remains underexplored. Here, we present a comparison of the ability of five water prediction programs (3D-RISM, SZMAP, WaterFLAP, WaterRank, and WaterMap) to predict crystallographic water locations, calculate their binding free energies, and to relate differences in these energies to observed changes in potency. The structural cohort included nine Bruton's Tyrosine Kinase (BTK) structures, and nine bromodomain structures. Each program accurately predicted the locations of most crystallographic water molecules. However, the predicted binding free energies correlated poorly with the observed changes in inhibitor potency when solvent atoms were displaced by chemical changes in closely related compounds.


Subject(s)
Agammaglobulinaemia Tyrosine Kinase/chemistry , Computer Simulation , Models, Molecular , Protein Kinase Inhibitors/chemistry , Water/chemistry , Crystallography, X-Ray , Ligands , Protein Binding , Protein Domains , Software , Solvents/chemistry , Structure-Activity Relationship , Thermodynamics
4.
Bioorg Med Chem Lett ; 25(2): 367-71, 2015 Jan 15.
Article in English | MEDLINE | ID: mdl-25466710

ABSTRACT

A rational fluorine scan based on co-crystal structures was explored to increase the potency of a series of selective BTK inhibitors. While fluorine substitution on a saturated bicyclic ring system yields no apparent benefit, the same operation on an unsaturated bicyclic ring can increase HWB activity by up to 40-fold. Comparison of co-crystal structures of parent molecules and fluorinated counterparts revealed the importance of placing fluorine at the optimal position to achieve favorable interactions with protein side chains.


Subject(s)
Fluorine/chemistry , Fluorine/metabolism , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Protein-Tyrosine Kinases/chemistry , Protein-Tyrosine Kinases/metabolism , Agammaglobulinaemia Tyrosine Kinase , Crystallography, X-Ray , Humans , Models, Molecular , Molecular Structure , Protein Conformation , Structure-Activity Relationship
5.
Bioorg Med Chem Lett ; 24(21): 4969-75, 2014 Nov 01.
Article in English | MEDLINE | ID: mdl-25262541

ABSTRACT

The discovery of a novel series of pyrrolopyrazines as JAK inhibitors with comparable enzyme and cellular activity to tofacitinib is described. The series was identified using a scaffold hopping approach aided by structure based drug design using principles of intramolecular hydrogen bonding for conformational restriction and targeting specific pockets for modulating kinase activity.


Subject(s)
Janus Kinase 3/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Pyrazines/chemistry , Pyrroles/chemistry , Drug Design , Humans , Janus Kinase 3/metabolism , Models, Molecular , Molecular Conformation , Molecular Structure , Phosphorylation , Piperidines/pharmacology , Pyrimidines/pharmacology , Pyrroles/pharmacology , Structure-Activity Relationship
6.
Acta Crystallogr D Biol Crystallogr ; 69(Pt 9): 1717-25, 2013 Sep.
Article in English | MEDLINE | ID: mdl-23999295

ABSTRACT

XIAP, a member of the inhibitor of apoptosis family of proteins, is a critical regulator of apoptosis. Inhibition of the BIR domain-caspase interaction is a promising approach towards treating cancer. Previous work has been directed towards inhibiting the BIR3-caspase-9 interaction, which blocks the intrinsic apoptotic pathway; selectively inhibiting the BIR2-caspase-3 interaction would also block the extrinsic pathway. The BIR2 domain of XIAP has successfully been crystallized; peptides and small-molecule inhibitors can be soaked into these crystals, which diffract to high resolution. Here, the BIR2 apo crystal structure and the structures of five BIR2-tetrapeptide complexes are described. The structural flexibility observed on comparing these structures, along with a comparison with XIAP BIR3, affords an understanding of the structural elements that drive selectivity between BIR2 and BIR3 and which can be used to design BIR2-selective inhibitors.


Subject(s)
Caspase 3/chemistry , Caspase 3/metabolism , Caspase Inhibitors/chemistry , Inhibitor of Apoptosis Proteins/chemistry , Nucleopolyhedroviruses/chemistry , Viral Proteins/chemistry , X-Linked Inhibitor of Apoptosis Protein/chemistry , Amino Acid Sequence , Apoproteins/chemistry , Apoproteins/genetics , Apoptosis/genetics , Crystallography, X-Ray , Humans , Inhibitor of Apoptosis Proteins/genetics , Molecular Sequence Data , Multigene Family/genetics , Nucleopolyhedroviruses/genetics , Oligopeptides/chemistry , Oligopeptides/genetics , Protein Interaction Mapping , Protein Structure, Tertiary/genetics , Viral Proteins/genetics , X-Linked Inhibitor of Apoptosis Protein/genetics
7.
Acta Crystallogr D Biol Crystallogr ; 69(Pt 6): 1124-37, 2013 Jun.
Article in English | MEDLINE | ID: mdl-23695257

ABSTRACT

The aspartic protease BACE2 is responsible for the shedding of the transmembrane protein Tmem27 from the surface of pancreatic ß-cells, which leads to inactivation of the ß-cell proliferating activity of Tmem27. This role of BACE2 in the control of ß-cell maintenance suggests BACE2 as a drug target for diabetes. Inhibition of BACE2 has recently been shown to lead to improved control of glucose homeostasis and to increased insulin levels in insulin-resistant mice. BACE2 has 52% sequence identity to the well studied Alzheimer's disease target enzyme ß-secretase (BACE1). High-resolution BACE2 structures would contribute significantly to the investigation of this enzyme as either a drug target or anti-target. Surface mutagenesis, BACE2-binding antibody Fab fragments, single-domain camelid antibody VHH fragments (Xaperones) and Fyn-kinase-derived SH3 domains (Fynomers) were used as crystallization helpers to obtain the first high-resolution structures of BACE2. Eight crystal structures in six different packing environments define an ensemble of low-energy conformations available to the enzyme. Here, the different strategies used for raising and selecting BACE2 binders for cocrystallization are described and the crystallization success, crystal quality and the time and resources needed to obtain suitable crystals are compared.


Subject(s)
Amyloid Precursor Protein Secretases/chemistry , Aspartic Acid Endopeptidases/chemistry , Immunoglobulin Fab Fragments/chemistry , Insulin-Secreting Cells/enzymology , Amyloid Precursor Protein Secretases/genetics , Amyloid Precursor Protein Secretases/metabolism , Animals , Area Under Curve , Aspartic Acid Endopeptidases/genetics , Aspartic Acid Endopeptidases/metabolism , Catalytic Domain , Crystallization , Humans , Immunoglobulin Fab Fragments/metabolism , Insulin-Secreting Cells/metabolism , Mice , Models, Molecular , Mutagenesis , Protein Conformation , Surface Plasmon Resonance , X-Ray Diffraction
8.
Bioorg Med Chem Lett ; 23(9): 2522-6, 2013 May 01.
Article in English | MEDLINE | ID: mdl-23541670

ABSTRACT

We report the discovery of a novel series of ATP-competitive Janus kinase 3 (JAK3) inhibitors based on the 5H-pyrrolo[2,3-b]pyrazine scaffold. The initial leads in this series, compounds 1a and 1h, showed promising potencies, but a lack of selectivity against other isoforms in the JAK family. Computational and crystallographic analysis suggested that the phenyl ether moiety possessed a favorable vector to achieve selectivity. Exploration of this vector resulted in the identification of 12b and 12d, as potent JAK3 inhibitors, demonstrating improved JAK family and kinase selectivity.


Subject(s)
Janus Kinase 3/antagonists & inhibitors , Phenyl Ethers/chemistry , Protein Kinase Inhibitors/chemistry , Pyridazines/chemistry , Pyrroles/chemistry , Binding Sites , Catalytic Domain , Drug Evaluation, Preclinical , Janus Kinase 3/metabolism , Molecular Docking Simulation , Phenyl Ethers/chemical synthesis , Phenyl Ethers/metabolism , Protein Binding , Protein Isoforms/antagonists & inhibitors , Protein Isoforms/metabolism , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/metabolism , Structure-Activity Relationship
9.
Bioorg Med Chem Lett ; 23(9): 2793-800, 2013 May 01.
Article in English | MEDLINE | ID: mdl-23540648

ABSTRACT

Using a structure based design approach we have identified a series of indazole substituted pyrrolopyrazines, which are potent inhibitors of JAK3. Intramolecular electronic repulsion was used as a strategy to induce a strong conformational bias within the ligand. Compounds bearing this conformation participated in a favorable hydrophobic interaction with a cysteine residue in the JAK3 binding pocket, which imparted high selectivity versus the kinome and improved selectivity within the JAK family.


Subject(s)
Drug Design , Janus Kinase 3/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Binding Sites , Crystallography, X-Ray , Hydrophobic and Hydrophilic Interactions , Indazoles/chemistry , Janus Kinase 1/antagonists & inhibitors , Janus Kinase 1/metabolism , Janus Kinase 2/antagonists & inhibitors , Janus Kinase 2/metabolism , Janus Kinase 3/metabolism , Molecular Docking Simulation , Protein Binding , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/metabolism , Protein Structure, Tertiary , Pyrazines/chemical synthesis , Pyrazines/chemistry , Pyrazines/metabolism , Structure-Activity Relationship
10.
Bioorg Med Chem Lett ; 23(12): 3565-9, 2013 Jun 15.
Article in English | MEDLINE | ID: mdl-23664880

ABSTRACT

A novel series of indole/indazole-aminopyrimidines was designed and synthesized with an aim to achieve optimal potency and selectivity for the c-Jun kinase family or JNKs. Structure guided design was used to optimize the series resulting in a significant potency improvement. The best compound (17) has IC50 of 3 nM for JNK1 and 20 nM for JNK2, with greater than 40-fold selectivity against other kinases with good physicochemical and pharmacokinetic properties.


Subject(s)
Indoles/chemistry , Indoles/pharmacology , JNK Mitogen-Activated Protein Kinases/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Pyrimidines/chemistry , Pyrimidines/pharmacology , Crystallography, X-Ray , Indazoles/chemistry , Indazoles/pharmacology , JNK Mitogen-Activated Protein Kinases/chemistry , Phosphorylation , Structure-Activity Relationship
11.
Bioorg Med Chem Lett ; 23(5): 1486-92, 2013 Mar 01.
Article in English | MEDLINE | ID: mdl-23352510

ABSTRACT

A series of amino-pyrimidines was developed based upon an initial kinase cross-screening hit from a CDK2 program. Kinase profiling and structure-based drug design guided the optimization from the initial 1,2,3-benzotriazole hit to a potent and selective JNK inhibitor, compound 24f (JNK1 and 2 IC(50)=16 and 66 nM, respectively), with bioavailability in rats and suitable for further in vivo pharmacological evaluation.


Subject(s)
JNK Mitogen-Activated Protein Kinases/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Pyrimidines/chemistry , Pyrimidines/pharmacology , Triazoles/chemistry , Triazoles/pharmacology , Animals , Crystallography, X-Ray , Drug Design , Humans , JNK Mitogen-Activated Protein Kinases/metabolism , Models, Molecular , Protein Kinase Inhibitors/chemical synthesis , Pyrimidines/chemical synthesis , Rats , Structure-Activity Relationship , Triazoles/chemical synthesis
12.
Acta Crystallogr D Biol Crystallogr ; 68(Pt 8): 893-900, 2012 Aug.
Article in English | MEDLINE | ID: mdl-22868754

ABSTRACT

Focused acoustic energy allows accurate and precise liquid transfer on scales from picolitre to microlitre volumes. This technology was applied in protein crystallization, successfully transferring a diverse set of proteins as well as hundreds of precipitant solutions from custom and commercial crystallization screens and achieving crystallization in drop volumes as small as 20 nl. Only higher concentrations (>50%) of 2-methyl-2,4-pentanediol (MPD) appeared to be systematically problematic in delivery. The acoustic technology was implemented in a workflow, successfully reproducing active crystallization systems and leading to the discovery of crystallization conditions for previously uncharacterized proteins. The technology offers compelling advantages in low-nanolitre crystallization trials by providing significant reagent savings and presenting seamless scalability for those crystals that require larger volume optimization experiments using the same vapor-diffusion format.


Subject(s)
Crystallization , Crystallography, X-Ray/methods , Acoustics , Animals , Chickens , Egg White/chemistry , Glycols/chemistry , HIV Reverse Transcriptase/chemistry , Hepacivirus/metabolism , Humans , Muramidase/chemistry , Nanoparticles , Nanotechnology/methods , Protein-Tyrosine Kinases/chemistry , Proteins/chemistry , Serum Albumin/chemistry , Viral Proteins/chemistry , Viscosity
13.
Bioorg Med Chem Lett ; 22(24): 7381-7, 2012 Dec 15.
Article in English | MEDLINE | ID: mdl-23142618

ABSTRACT

A novel series of highly selective JNK inhibitors based on the 4-quinolone scaffold was designed and synthesized. Structure based drug design was utilized to guide the compound design as well as improvements in the physicochemical properties of the series. Compound (13c) has an IC(50) of 62/170 nM for JNK1/2, excellent kinase selectivity and impressive efficacy in a rodent asthma model.


Subject(s)
4-Quinolones/pharmacology , Drug Discovery , JNK Mitogen-Activated Protein Kinases/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , 4-Quinolones/chemical synthesis , 4-Quinolones/chemistry , Crystallography, X-Ray , Dose-Response Relationship, Drug , Humans , JNK Mitogen-Activated Protein Kinases/metabolism , Models, Molecular , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Structure-Activity Relationship
14.
J Med Chem ; 65(19): 13052-13073, 2022 10 13.
Article in English | MEDLINE | ID: mdl-36178776

ABSTRACT

Addressing resistance to third-generation EGFR TKIs such as osimertinib via the EGFRC797S mutation remains a highly unmet need in EGFR-driven non-small-cell lung cancer (NSCLC). Herein, we present the discovery of the allosteric EGFR inhibitor 57, a novel fourth-generation inhibitor to overcome EGFRC797S-mediated resistance in patients harboring the activating EGFRL858R mutation. 57 exhibits an improved potency compared to previous allosteric EGFR inhibitors. To our knowledge, 57 is the first allosteric EGFR inhibitor that demonstrates robust tumor regression in a mutant EGFRL858R/C797S tumor model. Additionally, 57 is active in an H1975 EGFRL858R/T790M NSCLC xenograft model and shows superior efficacy in combination with osimertinib compared to the single agents. Our data highlight the potential of 57 as a single agent against EGFRL858R/C797S and EGFRL858R/T790M/C797S and as combination therapy for EGFRL858R- and EGFRL858R/T790M-driven NSCLC.


Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Acrylamides , Aniline Compounds/pharmacology , Aniline Compounds/therapeutic use , Carcinoma, Non-Small-Cell Lung/pathology , Drug Resistance, Neoplasm , ErbB Receptors/genetics , Humans , Indoles , Lung Neoplasms/pathology , Mutation , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Pyrimidines
15.
Acta Crystallogr D Biol Crystallogr ; 67(Pt 2): 119-23, 2011 Feb.
Article in English | MEDLINE | ID: mdl-21245533

ABSTRACT

E-ISA247 (voclosporin) is a cyclosporin A analogue that is in late-stage clinical development for the treatment of autoimmune diseases and the prevention of organ graft rejection. The X-ray crystal structures of E-ISA247 and its stereoisomer Z-ISA247 bound to cyclophilin A have been determined and their binding affinities were measured to be 15 and 61 nM, respectively, by fluorescence spectroscopy. The higher affinity of E-ISA247 can be explained by superior van der Waals contacts between its unique side chain and cyclophilin A. Comparison with the known ternary structure including calcineurin suggests that the higher immunosuppressive efficacy of E-ISA247 relative to cyclosporin A could be a consequence of structural changes in calcineurin induced by the modified E-ISA247 side chain.


Subject(s)
Cyclophilin A/chemistry , Cyclosporine/chemistry , Immunosuppressive Agents/chemistry , Crystallography, X-Ray , Cyclophilin A/metabolism , Cyclosporine/metabolism , Humans , Immunosuppressive Agents/metabolism , Isomerism , Models, Molecular , Protein Binding , Protein Structure, Tertiary
17.
Acta Crystallogr D Biol Crystallogr ; 66(Pt 5): 568-76, 2010 May.
Article in English | MEDLINE | ID: mdl-20445232

ABSTRACT

A crystal seeding technique is introduced that uses acoustic waves to deliver nanolitre volumes of seed suspension into protein drops. The reduction in delivery volume enables enhanced crystal growth in matrix-seeding experiments without concern for bias from chemical components in the seed-carrying buffer suspension. Using this technique, it was found that while buffer components alone without seed can marginally promote crystal growth in some cases, crystal seeding is far more effective in boosting the number of sparse-matrix conditions that yield protein crystals.


Subject(s)
Crystallization/methods , Proteins/chemistry , Humans
18.
Bioorg Med Chem Lett ; 20(17): 5217-20, 2010 Sep 01.
Article in English | MEDLINE | ID: mdl-20655210

ABSTRACT

JNK2 and p38alpha are closely related mitogen-activated protein kinases that regulate various cellular activities and are considered drug targets for inflammatory diseases. We have determined the X-ray crystal structure of the clinical phase II p38alpha inhibitor BIRB796 bound to its off-target JNK2. This shows for the first time a JNK subfamily member in the DFG-out conformation. The fully resolved activation loop reveals that BIRB796 inhibits JNK2 activation by stabilizing the loop in a position that does not allow its phosphorylation by upstream kinases. The structure suggests that substituents at the BIRB796 morpholino group and modifications of the t-butyl moiety should further increase the p38alpha to JNK2 potency ratio. For the design of selective DFG-out binding JNK2 inhibitors, the binding pocket of the BIRB796 tolyl group may have the best potential.


Subject(s)
Mitogen-Activated Protein Kinase 9/chemistry , Mitogen-Activated Protein Kinases/chemistry , Naphthalenes/chemistry , Protein Kinase Inhibitors/chemistry , Pyrazoles/chemistry , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , Crystallography, X-Ray , Drug Design , Models, Molecular , Molecular Structure
19.
Nat Commun ; 11(1): 4974, 2020 10 02.
Article in English | MEDLINE | ID: mdl-33009381

ABSTRACT

Generation of bispecific antibodies (bsAbs) requires a combination of compatible binders in formats that support desired functionalities. Here, we report that bsAb-matrices can be generated by Format Chain Exchange (FORCE), enabling screening of combinatorial binder/format spaces. Input molecules for generation of bi/multi-valent bsAbs are monospecific entities similar to knob-into-hole half-antibodies, yet with complementary CH3-interface-modulated and affinity-tagged dummy-chains. These contain mutations that lead to limited interface repulsions without compromising expression or biophysical properties of educts. Mild reduction of combinations of educts triggers spontaneous chain-exchange reactions driven by partially flawed CH3-educt interfaces resolving to perfect complementarity. This generates large bsAb matrices harboring different binders in multiple formats. Benign biophysical properties and good expression yields of educts, combined with simplicity of purification enables process automation. Examples that demonstrate the relevance of screening binder/format combinations are provided as a matrix of bsAbs that simultaneously bind Her1/Her2 and DR5 without encountering binder or format-inflicted interferences.


Subject(s)
Antibodies, Bispecific/biosynthesis , High-Throughput Screening Assays , Antibodies, Bispecific/isolation & purification , Automation , HEK293 Cells , Humans , Mutation/genetics , Protein Multimerization
20.
J Med Chem ; 63(13): 6876-6897, 2020 07 09.
Article in English | MEDLINE | ID: mdl-32530624

ABSTRACT

Aldosterone synthase (CYP11B2) inhibitors have been explored in recent years as an alternative therapeutic option to mineralocorticoid receptor (MR) antagonists to reduce elevated aldosterone levels, which are associated with deleterious effects on various organ systems including the heart, vasculature, kidney, and central nervous system (CNS). A benzamide pyridine hit derived from a focused screen was successfully developed into a series of potent and selective 3-pyridyl isoindolin-1-ones CYP11B2 inhibitors. Our systematic structure-activity relationship study enabled us to identify unique structural features that result in high selectivity against the closely homologous cortisol synthase (CYP11B1). We evaluated advanced lead molecules, exemplified by compound 52, in an in vivo cynomolgus monkey acute adrenocorticotropic hormone (ACTH) challenge model and demonstrated a superior 100-fold in vivo selectivity against CYP11B1.


Subject(s)
Cytochrome P-450 CYP11B2/antagonists & inhibitors , Cytochrome P-450 Enzyme Inhibitors/chemistry , Cytochrome P-450 Enzyme Inhibitors/pharmacology , Drug Design , Isoindoles/chemistry , Pyridines/chemistry , Pyridines/pharmacology , Administration, Oral , Animals , Cytochrome P-450 Enzyme Inhibitors/administration & dosage , Cytochrome P-450 Enzyme Inhibitors/pharmacokinetics , Drug Stability , Humans , Models, Molecular , Molecular Conformation , Pyridines/administration & dosage , Pyridines/pharmacokinetics , Rats , Structure-Activity Relationship , Tissue Distribution
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