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1.
J Med Chem ; 62(22): 10258-10271, 2019 11 27.
Article in English | MEDLINE | ID: mdl-31736296

ABSTRACT

Overexpression of the antiapoptotic protein Mcl-1 provides a survival advantage to some cancer cells, making inhibition of this protein an attractive therapeutic target for the treatment of certain types of tumors. Herein, we report our efforts toward the identification of a novel series of macrocyclic Mcl-1 inhibitors featuring an α-hydroxy phenylacetic acid pharmacophore or bioisostere. This work led to the discovery of 1, a potent Mcl-1 inhibitor (IC50 = 19 nM in an OPM-2 cell viability assay) with good pharmacokinetic properties and excellent in vivo efficacy in an OPM-2 multiple myeloma xenograft model.


Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Myeloid Cell Leukemia Sequence 1 Protein/antagonists & inhibitors , Phenylacetates/chemistry , Administration, Oral , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/pharmacokinetics , Biological Availability , Cell Line, Tumor , Crystallography, X-Ray , Drug Design , Drug Stability , Female , Humans , Hydrogen Bonding , Mice, Nude , Multiple Myeloma/drug therapy , Myeloid Cell Leukemia Sequence 1 Protein/chemistry , Myeloid Cell Leukemia Sequence 1 Protein/metabolism , Rats, Sprague-Dawley , Structure-Activity Relationship , Sulfonamides/chemistry , Xenograft Model Antitumor Assays
2.
J Med Chem ; 62(14): 6751-6764, 2019 07 25.
Article in English | MEDLINE | ID: mdl-31274313

ABSTRACT

Structure-based modification of mifepristone (1) led to the discovery of novel mifepristone derivatives with improved selectivity profile. Addition of a methyl group at the C10 position of the steroid has a significant impact on progesterone receptor (PR) and androgen receptor (AR) activity. Within this series, OP-3633 (15) emerged as a glucocorticoid receptor (GR) antagonist with increased selectivity against PR and AR, improved cytochrome P450 inhibition profile, and significantly improved pharmacokinetic properties compared to 1. Furthermore, 15 demonstrated substantial inhibition of GR transcriptional activity in the GR positive HCC1806 triple negative breast cancer xenograft model. Overall, compound 15 is a promising GR antagonist candidate to clinically evaluate the impact of GR inhibition in reversal or prevention of therapy resistance.


Subject(s)
Mifepristone/analogs & derivatives , Mifepristone/pharmacology , Receptors, Glucocorticoid/antagonists & inhibitors , Androgen Receptor Antagonists/chemistry , Androgen Receptor Antagonists/pharmacology , Drug Discovery , Humans , Models, Molecular , Receptors, Androgen/metabolism , Receptors, Glucocorticoid/metabolism , Receptors, Progesterone/antagonists & inhibitors , Receptors, Progesterone/metabolism
3.
J Med Chem ; 61(17): 7767-7784, 2018 09 13.
Article in English | MEDLINE | ID: mdl-30091920

ABSTRACT

The glucocorticoid receptor (GR) has been linked to therapy resistance across a wide range of cancer types. Preclinical data suggest that antagonists of this nuclear receptor may enhance the activity of anticancer therapy. The first-generation GR antagonist mifepristone is currently undergoing clinical evaluation in various oncology settings. Structure-based modification of mifepristone led to the discovery of ORIC-101 (28), a highly potent steroidal GR antagonist with reduced androgen receptor (AR) agonistic activity amenable for dosing in androgen receptor positive tumors and with improved CYP2C8 and CYP2C9 inhibition profile to minimize drug-drug interaction potential. Unlike mifepristone, 28 could be codosed with chemotherapeutic agents readily metabolized by CYP2C8 such as paclitaxel. Furthermore, 28 demonstrated in vivo antitumor activity by enhancing response to chemotherapy in the GR+ OVCAR5 ovarian cancer xenograft model. Clinical evaluation of safety and therapeutic potential of 28 is underway.


Subject(s)
Drug Discovery , Hormone Antagonists/pharmacology , Ovarian Neoplasms/drug therapy , Receptors, Glucocorticoid/antagonists & inhibitors , Animals , Female , Hormone Antagonists/chemistry , Hormone Antagonists/pharmacokinetics , Humans , Mice , Ovarian Neoplasms/metabolism , Ovarian Neoplasms/pathology , Rats , Swine , Swine, Miniature , Tissue Distribution , Tumor Cells, Cultured , Xenograft Model Antitumor Assays
4.
J Med Chem ; 57(24): 10499-511, 2014 Dec 26.
Article in English | MEDLINE | ID: mdl-25384157

ABSTRACT

Structure-based rational design and extensive structure-activity relationship studies led to the discovery of AMG 232 (1), a potent piperidinone inhibitor of the MDM2-p53 association, which is currently being evaluated in human clinical trials for the treatment of cancer. Further modifications of 1, including replacing the carboxylic acid with a 4-amidobenzoic acid, afforded AM-7209 (25), featuring improved potency (KD from ITC competition was 38 pM, SJSA-1 EdU IC50 = 1.6 nM), remarkable pharmacokinetic properties, and in vivo antitumor activity in both the SJSA-1 osteosarcoma xenograft model (ED50 = 2.6 mg/kg QD) and the HCT-116 colorectal carcinoma xenograft model (ED50 = 10 mg/kg QD). In addition, 25 possesses distinct mechanisms of elimination compared to 1.


Subject(s)
Antineoplastic Agents/pharmacology , Cell Proliferation/drug effects , Colonic Neoplasms/drug therapy , Drug Discovery , Protein Binding/drug effects , Proto-Oncogene Proteins c-mdm2/antagonists & inhibitors , Tumor Suppressor Protein p53/antagonists & inhibitors , Animals , Antineoplastic Agents/chemistry , Colonic Neoplasms/metabolism , Colonic Neoplasms/pathology , Female , Humans , Mice , Mice, Nude , Models, Molecular , Molecular Structure , Proto-Oncogene Proteins c-mdm2/metabolism , Structure-Activity Relationship , Tumor Cells, Cultured , Tumor Suppressor Protein p53/metabolism
5.
ACS Med Chem Lett ; 5(11): 1245-50, 2014 Nov 13.
Article in English | MEDLINE | ID: mdl-25408839

ABSTRACT

In this letter, we reported the design and synthesis of three potent, selective, and orally bioavailable 11ß-HSD1 inhibitors labeled with (14)C: AMG 456 (1), AM-6949 (2), and AM-7715 (3). We evaluated the covalent protein binding of the labeled inhibitors in human liver microsomes in vitro and assessed their potential bioactivation risk in humans. We then studied the in vitro mechanism of 2 in human hepatocytes and the formation of reactive intermediates. Our study results suggest that 1 and 3 have low potential for metabolic bioactivation in humans, while 2 has relatively high risk.

6.
ACS Med Chem Lett ; 5(8): 894-9, 2014 Aug 14.
Article in English | MEDLINE | ID: mdl-25147610

ABSTRACT

Continued optimization of the N-substituent in the piperidinone series provided potent piperidinone-pyridine inhibitors 6, 7, 14, and 15 with improved pharmacokinetic properties in rats. Reducing structure complexity of the N-alkyl substituent led to the discovery of 23, a potent and simplified inhibitor of MDM2. Compound 23 exhibits excellent pharmacokinetic properties and substantial in vivo antitumor activity in the SJSA-1 osteosarcoma xenograft mouse model.

7.
J Med Chem ; 57(15): 6332-41, 2014 Aug 14.
Article in English | MEDLINE | ID: mdl-24967612

ABSTRACT

We recently reported the discovery of AMG 232 (1), a potent and selective piperidinone inhibitor of the MDM2-p53 protein-protein interaction. Compound 1 is currently being evaluated in human clinical trials for the treatment of cancer. This article provides an overview of its discovery from the de novo design of the piperidinone series to the structure-activity studies leading to the identification of 1. In addition, this article also describes the preclinical pharmacology and pharmacokinetics of 1, along with its drug metabolism and safety assessment.


Subject(s)
Acetates/chemistry , Antineoplastic Agents/chemistry , Piperidones/chemistry , Proto-Oncogene Proteins c-mdm2/antagonists & inhibitors , Acetates/adverse effects , Acetates/pharmacology , Animals , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacology , Binding Sites , Humans , Models, Molecular , Piperidones/adverse effects , Piperidones/pharmacology , Protein Binding , Protein Conformation , Structure-Activity Relationship
8.
J Med Chem ; 57(7): 2963-88, 2014 Apr 10.
Article in English | MEDLINE | ID: mdl-24601644

ABSTRACT

We previously reported the discovery of potent and selective morpholinone and piperidinone inhibitors of the MDM2-p53 interaction. These inhibitors have in common a carboxylic acid moiety that engages in an electrostatic interaction with MDM2-His96. Our continued search for potent and diverse inhibitors led to the discovery of novel replacements for these acids uncovering new interactions with the MDM2 protein. In particular, using pyridine or thiazole as isosteres of the carboxylic acid moiety resulted in very potent analogues. From these, AM-6761 (4) emerged as a potent inhibitor with remarkable biochemical (HTRF IC50 = 0.1 nM) and cellular potency (SJSA-1 EdU IC50 = 16 nM), as well as favorable pharmacokinetic properties. Compound 4 also shows excellent antitumor activity in the SJSA-1 osteosarcoma xenograft model with an ED50 of 11 mg/kg. Optimization efforts toward the discovery of these inhibitors as well as the new interactions observed with the MDM2 protein are described herein.


Subject(s)
Acetates/pharmacology , Antineoplastic Agents/pharmacology , Carboxylic Acids/pharmacology , Cell Proliferation/drug effects , Myocytes, Smooth Muscle/drug effects , Piperidones/pharmacology , Protein Interaction Domains and Motifs/drug effects , Proto-Oncogene Proteins c-mdm2/antagonists & inhibitors , Tumor Suppressor Protein p53/antagonists & inhibitors , Acetates/chemistry , Animals , Bone Neoplasms/drug therapy , Carboxylic Acids/chemistry , Cells, Cultured , Crystallography, X-Ray , Drug Design , Female , Humans , Hydrogen Bonding , Mice , Mice, Nude , Models, Molecular , Molecular Structure , Osteosarcoma/drug therapy , Piperidones/chemistry , Protein Binding , Proto-Oncogene Proteins c-mdm2/metabolism , Stereoisomerism , Structure-Activity Relationship , Tumor Cells, Cultured , Tumor Suppressor Protein p53/metabolism , Xenograft Model Antitumor Assays
9.
J Med Chem ; 57(6): 2472-88, 2014 Mar 27.
Article in English | MEDLINE | ID: mdl-24548297

ABSTRACT

We previously reported the discovery of AMG 232, a highly potent and selective piperidinone inhibitor of the MDM2-p53 interaction. Our continued search for potent and diverse analogues led to the discovery of novel morpholinone MDM2 inhibitors. This change to a morpholinone core has a significant impact on both potency and metabolic stability compared to the piperidinone series. Within this morpholinone series, AM-8735 emerged as an inhibitor with remarkable biochemical potency (HTRF IC50 = 0.4 nM) and cellular potency (SJSA-1 EdU IC50 = 25 nM), as well as pharmacokinetic properties. Compound 4 also shows excellent antitumor activity in the SJSA-1 osteosarcoma xenograft model with an ED50 of 41 mg/kg. Lead optimization toward the discovery of this inhibitor as well as key differences between the morpholinone and the piperidinone series will be described herein.


Subject(s)
Acetates/chemical synthesis , Acetates/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Morpholines/chemical synthesis , Morpholines/pharmacology , Proto-Oncogene Proteins c-mdm2/antagonists & inhibitors , Proto-Oncogene Proteins c-mdm2/chemistry , Tumor Suppressor Protein p53/antagonists & inhibitors , Tumor Suppressor Protein p53/chemistry , Animals , Cell Line, Tumor , Crystallography, X-Ray , Drug Discovery , Humans , Indicators and Reagents , Mice , Models, Molecular , Molecular Conformation , Morpholines/pharmacokinetics , Rats , Structure-Activity Relationship , Xenograft Model Antitumor Assays
10.
J Med Chem ; 57(4): 1454-72, 2014 Feb 27.
Article in English | MEDLINE | ID: mdl-24456472

ABSTRACT

We recently reported the discovery of AM-8553 (1), a potent and selective piperidinone inhibitor of the MDM2-p53 interaction. Continued research investigation of the N-alkyl substituent of this series, focused in particular on a previously underutilized interaction in a shallow cleft on the MDM2 surface, led to the discovery of a one-carbon tethered sulfone which gave rise to substantial improvements in biochemical and cellular potency. Further investigation produced AMG 232 (2), which is currently being evaluated in human clinical trials for the treatment of cancer. Compound 2 is an extremely potent MDM2 inhibitor (SPR KD = 0.045 nM, SJSA-1 EdU IC50 = 9.1 nM), with remarkable pharmacokinetic properties and in vivo antitumor activity in the SJSA-1 osteosarcoma xenograft model (ED50 = 9.1 mg/kg).


Subject(s)
Acetates/pharmacology , Antineoplastic Agents/pharmacology , Piperidones/pharmacology , Proto-Oncogene Proteins c-mdm2/antagonists & inhibitors , Tumor Suppressor Protein p53/antagonists & inhibitors , Acetates/chemistry , Administration, Oral , Antineoplastic Agents/chemistry , Biological Availability , Crystallography, X-Ray , Drug Discovery , Humans , Piperidones/chemistry , Protein Conformation
11.
J Med Chem ; 56(10): 4053-70, 2013 May 23.
Article in English | MEDLINE | ID: mdl-23597064

ABSTRACT

Structural analysis of both the MDM2-p53 protein-protein interaction and several small molecules bound to MDM2 led to the design and synthesis of tetrasubstituted morpholinone 10, an MDM2 inhibitor with a biochemical IC50 of 1.0 µM. The cocrystal structure of 10 with MDM2 inspired two independent optimization strategies and resulted in the discovery of morpholinones 16 and 27 possessing distinct binding modes. Both analogues were potent MDM2 inhibitors in biochemical and cellular assays, and morpholinone 27 (IC50 = 0.10 µM) also displayed suitable PK profile for in vivo animal experiments. A pharmacodynamic (PD) experiment in mice implanted with human SJSA-1 tumors showed p21(WAF1) mRNA induction (2.7-fold over vehicle) upon oral dosing of 27 at 300 mg/kg.


Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Proto-Oncogene Proteins c-mdm2/antagonists & inhibitors , Tumor Suppressor Protein p53/antagonists & inhibitors , Animals , Circular Dichroism , Crystallography , Crystallography, X-Ray , Drug Design , Female , Humans , Indicators and Reagents , Mice , Mice, Nude , Models, Molecular , Morpholines/chemical synthesis , Morpholines/pharmacology , Piperidines/chemical synthesis , Piperidines/pharmacology , Stereoisomerism , Structure-Activity Relationship , Xenograft Model Antitumor Assays
12.
J Am Chem Soc ; 134(41): 17059-67, 2012 Oct 17.
Article in English | MEDLINE | ID: mdl-22991965

ABSTRACT

Restoration of p53 function through the disruption of the MDM2-p53 protein complex is a promising strategy for the treatment of various types of cancer. Here, we present kinetic, thermodynamic, and structural rationale for the remarkable potency of a new class of MDM2 inhibitors, the piperidinones. While these compounds bind to the same site as previously reported for small molecule inhibitors, such as the Nutlins, data presented here demonstrate that the piperidinones also engage the N-terminal region (residues 10-16) of human MDM2, in particular, Val14 and Thr16. This portion of MDM2 is unstructured in both the apo form of the protein and in MDM2 complexes with p53 or Nutlin, but adopts a novel ß-strand structure when complexed with the piperidinones. The ordering of the N-terminus upon binding of the piperidinones extends the current model of MDM2-p53 interaction and provides a new route to rational design of superior inhibitors.


Subject(s)
Piperidines/pharmacology , Proto-Oncogene Proteins c-mdm2/antagonists & inhibitors , Crystallography, X-Ray , Humans , Kinetics , Magnetic Resonance Spectroscopy , Models, Molecular , Molecular Structure , Piperidines/chemical synthesis , Piperidines/chemistry , Structure-Activity Relationship , Thermodynamics
13.
Bioorg Med Chem Lett ; 22(11): 3786-90, 2012 Jun 01.
Article in English | MEDLINE | ID: mdl-22542009

ABSTRACT

A novel series of benzenesulfonanilide derivatives of 11ß-HSD1 inhibitors were identified via modification of the sulfonamide core of the arylsulfonylpiperazine lead structures. The synthesis, in vitro biological evaluation, and structure-activity relationship of these compounds are presented. Optimization of this series rapidly resulted in the discovery of compounds (S)-10 and (S)-23 (11ß-HSD1 SPA IC(50)=1.8 and 1.4 nM, respectively).


Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1/antagonists & inhibitors , Anilides/chemistry , Aniline Compounds/chemistry , Enzyme Inhibitors/chemistry , Piperazines/chemistry , Sulfonamides/chemistry , 11-beta-Hydroxysteroid Dehydrogenase Type 1/genetics , 11-beta-Hydroxysteroid Dehydrogenase Type 1/metabolism , 11-beta-Hydroxysteroid Dehydrogenase Type 1/pharmacology , Anilides/chemical synthesis , Aniline Compounds/chemical synthesis , Aniline Compounds/pharmacology , Crystallography, X-Ray , Drug Evaluation, Preclinical , Enzyme Activation/drug effects , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , HEK293 Cells , Humans , Molecular Conformation , Piperazine , Piperazines/chemical synthesis , Piperazines/pharmacology , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/pharmacology , Transfection
14.
J Med Chem ; 55(11): 4936-54, 2012 Jun 14.
Article in English | MEDLINE | ID: mdl-22524527

ABSTRACT

Structure-based rational design led to the discovery of novel inhibitors of the MDM2-p53 protein-protein interaction. The affinity of these compounds for MDM2 was improved through conformational control of both the piperidinone ring and the appended N-alkyl substituent. Optimization afforded 29 (AM-8553), a potent and selective MDM2 inhibitor with excellent pharmacokinetic properties and in vivo efficacy.


Subject(s)
Acetates/chemical synthesis , Antineoplastic Agents/chemical synthesis , Piperidones/chemical synthesis , Proto-Oncogene Proteins c-mdm2/metabolism , Tumor Suppressor Protein p53/metabolism , Acetates/pharmacokinetics , Acetates/pharmacology , Animals , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Crystallography, X-Ray , Drug Screening Assays, Antitumor , Hepatocytes/metabolism , Humans , Macaca fascicularis , Mice , Mice, Nude , Models, Molecular , Molecular Conformation , Neoplasm Transplantation , Piperidones/pharmacokinetics , Piperidones/pharmacology , Protein Binding , Rats , Stereoisomerism , Structure-Activity Relationship , Transplantation, Heterologous , rho GTP-Binding Proteins/biosynthesis
15.
Bioorg Med Chem Lett ; 21(9): 2752-5, 2011 May 01.
Article in English | MEDLINE | ID: mdl-21123063

ABSTRACT

Human murine double minute 2 (MDM2) is a negative regulator of p53, which plays an important role in cell cycle and apoptosis. We report several optimizations to the synthesis of the chromenotriazolopyrimidine series of MDM2-p53 protein-protein interaction inhibitors. Additionally, the in vitro and in vivo stability, pharmacokinetic properties and solubility were improved through N-substitution.


Subject(s)
Proto-Oncogene Proteins c-mdm2/antagonists & inhibitors , Pyrimidines/chemical synthesis , Tumor Suppressor Protein p53/antagonists & inhibitors , Animals , Drug Stability , Humans , Infusion Pumps , Inhibitory Concentration 50 , Molecular Structure , Pyrimidines/pharmacokinetics , Rats , Solubility , Structure-Activity Relationship
17.
Bioorg Med Chem Lett ; 19(21): 6189-91, 2009 Nov 01.
Article in English | MEDLINE | ID: mdl-19783144

ABSTRACT

Ramoplanin is a potent lipoglycodepsipeptide antibiotic that is active against a wide range of Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococcus (VRE). It acts as an inhibitor of peptidoglycan (PG) biosynthesis that disrupts glycan chain polymerization by binding and sequestering Lipid II, a PG precursor. Herein, we report the functional antimicrobial activity (MIC, S. aureus) and fundamental biochemical assessments against a peptidoglycan glycosyltransferase (Escherichia coli PBP1b) of a set of key alanine scan analogues of ramoplanin that provide insight into the importance and role of each of its individual amino acid residues.


Subject(s)
Anti-Bacterial Agents/chemistry , Depsipeptides/chemistry , Anti-Bacterial Agents/pharmacology , Depsipeptides/pharmacology , Drug Resistance, Multiple, Bacterial/drug effects , Escherichia coli/enzymology , Gram-Positive Bacteria/drug effects , Peptidoglycan Glycosyltransferase/antagonists & inhibitors , Peptidoglycan Glycosyltransferase/metabolism
18.
Bioorg Med Chem Lett ; 19(6): 1797-801, 2009 Mar 15.
Article in English | MEDLINE | ID: mdl-19217779

ABSTRACT

Discovery and optimization of a piperidyl benzamide series of 11beta-HSD1 inhibitors is described. This series was derived from a cyclohexyl benzamide lead structures to address PXR selectivity, high non-specific protein binding, poor solubility, limited in vivo exposure, and in vitro cytotoxicity issues observed with the cyclohexyl benzamide structures. These efforts led to the discovery of piperidyl benzamide 15 which features improved properties over the cyclohexyl benzamide derivatives.


Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1/antagonists & inhibitors , Benzamides/chemical synthesis , Diabetes Mellitus, Type 2/drug therapy , Insulin/metabolism , Piperidines/chemistry , 11-beta-Hydroxysteroid Dehydrogenase Type 1/chemistry , Benzamides/pharmacology , Crystallography, X-Ray/methods , Drug Design , Hepatocytes/drug effects , Humans , Inhibitory Concentration 50 , Microsomes/metabolism , Models, Chemical , Molecular Structure , Solubility , Structure-Activity Relationship
19.
Bioorg Med Chem Lett ; 19(5): 1446-50, 2009 Mar 01.
Article in English | MEDLINE | ID: mdl-19185488

ABSTRACT

Novel 4,4-disubstituted cyclohexylbenzamide inhibitors of 11beta-HSD1 were optimized to account for liabilities relating to in vitro pharmacokinetics, cytotoxicity and protein-related shifts in potency. A representative compound showing favorable in vivo pharmacokinetics was found to be an efficacious inhibitor of 11beta-HSD1 in a rat pharmacodynamic model (ED(50)=10mg/kg).


Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1/antagonists & inhibitors , Benzamides/chemistry , 11-beta-Hydroxysteroid Dehydrogenase Type 1/metabolism , Animals , Benzamides/pharmacology , Dose-Response Relationship, Drug , HeLa Cells , Humans , Macaca fascicularis , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship
20.
J Med Chem ; 51(13): 3953-60, 2008 Jul 10.
Article in English | MEDLINE | ID: mdl-18553955

ABSTRACT

We report the discovery of potent benzamide inhibitors of 11beta-hydroxysteroid dehydrogenase (11beta-HSD1). The optimization and correlation of in vitro and in vivo metabolic stability will be described. Through modifications to our initial lead 2, we discovered pyridyl compound 13. This compound has a favorable pharmacokinetic profile across three species and showed a dose-dependent decrease in adipose 11beta-HSD1 activity in a monkey ex vivo pharmacodynamic model.


Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1/antagonists & inhibitors , Benzamides/administration & dosage , Benzamides/chemical synthesis , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/chemical synthesis , 11-beta-Hydroxysteroid Dehydrogenase Type 1/chemistry , 11-beta-Hydroxysteroid Dehydrogenase Type 1/metabolism , Administration, Oral , Animals , Benzamides/chemistry , Benzamides/metabolism , Cell Line , Crystallography, X-Ray , Dogs , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/metabolism , Humans , Macaca fascicularis , Models, Animal , Models, Molecular , Molecular Structure , Rats , Structure-Activity Relationship
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