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1.
Bioorg Med Chem ; 63: 116729, 2022 06 01.
Article in English | MEDLINE | ID: mdl-35439688

ABSTRACT

In this article, we report the discovery of a series of pyrimidopyridones as inhibitors of IRAK4 kinase. From a previously disclosed 5-azaquinazoline series, we found that switching the pyridine ring for an N-substituted pyridone gave a novel hinge binding scaffold which retained potency against IRAK4. Importantly, introduction of the carbonyl established an internal hydrogen bond with the 4-NH, establishing a conformational lock and allowing truncation of the large basic substituent to a 1-methylcyclopyl group. Subsequent optimisation, facilitated by X-ray crystal structures, allowed identification of preferred substituents at both the pyridone core and pyrazole. Subsequent combinations of optimal groups allowed control of lipophilicity and identification of potent and selective inhibitors of IRAK4 with better in vitro permeability and lower clearance.


Subject(s)
Interleukin-1 Receptor-Associated Kinases , Pyridones , Molecular Conformation , Pyridones/pharmacology , Structure-Activity Relationship
2.
J Med Chem ; 62(3): 1593-1608, 2019 02 14.
Article in English | MEDLINE | ID: mdl-30640465

ABSTRACT

Herein, we report the identification and synthesis of a series of tricyclic indazoles as a novel class of selective estrogen receptor degrader antagonists. Replacement of a phenol, present in our previously reported tetrahydroisoquinoline scaffold, with an indazole group led to the removal of a reactive metabolite signal in an in vitro glutathione trapping assay. Further optimization, guided by X-ray crystal structures and NMR conformational work, varied the alkyl side chain and pendant aryl group and resulted in compounds with low turnover in human hepatocytes and enhanced chemical stability. Compound 9 was profiled as a representative of the series in terms of pharmacology and demonstrated the desired estrogen receptor α degrader-antagonist profile and demonstrated activity in a xenograft model of breast cancer.


Subject(s)
Antineoplastic Agents/therapeutic use , Breast Neoplasms/drug therapy , Estrogen Receptor Antagonists/therapeutic use , Heterocyclic Compounds, 3-Ring/therapeutic use , Indazoles/therapeutic use , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacokinetics , Dogs , Drug Screening Assays, Antitumor , Estrogen Receptor Antagonists/chemical synthesis , Estrogen Receptor Antagonists/pharmacokinetics , Estrogen Receptor alpha/metabolism , Heterocyclic Compounds, 3-Ring/chemical synthesis , Heterocyclic Compounds, 3-Ring/pharmacokinetics , Humans , Indazoles/chemical synthesis , Indazoles/pharmacokinetics , MCF-7 Cells , Male , Mice, SCID , Microsomes, Liver/metabolism , Molecular Structure , Rats , Structure-Activity Relationship , Xenograft Model Antitumor Assays
3.
Bioorg Med Chem ; 26(4): 913-924, 2018 02 15.
Article in English | MEDLINE | ID: mdl-29398441

ABSTRACT

We have developed a series of orally efficacious IRAK4 inhibitors, based on a scaffold hopping strategy and using rational structure based design. Efforts to tackle low permeability and high efflux in our previously reported pyrrolopyrimidine series (Scott et al., 2017) led to the identification of pyrrolotriazines which contained one less formal hydrogen bond donor and were intrinsically more lipophilic. Further optimisation of substituents on this pyrrolotriazine core culminated with the discovery of 30 as a promising in vivo probe to assess the potential of IRAK4 inhibition for the treatment of MyD88 mutant DLBCL in combination with a BTK inhibitor. When tested in an ABC-DLBCL model with a dual MyD88/CD79 mutation (OCI-LY10), 30 demonstrated tumour regressions in combination with ibrutinib.


Subject(s)
Interleukin-1 Receptor-Associated Kinases/antagonists & inhibitors , Pyrroles/chemistry , Thiazines/chemistry , Animals , Binding Sites , Caco-2 Cells , Dogs , Drug Design , Half-Life , Hepatocytes/cytology , Hepatocytes/metabolism , Humans , Interleukin-1 Receptor-Associated Kinases/metabolism , Lymphoma, Large B-Cell, Diffuse/metabolism , Lymphoma, Large B-Cell, Diffuse/pathology , Molecular Dynamics Simulation , Mutation , Myeloid Differentiation Factor 88/genetics , Myeloid Differentiation Factor 88/metabolism , Permeability/drug effects , Protein Kinases/chemistry , Protein Kinases/metabolism , Pyrroles/pharmacokinetics , Pyrroles/pharmacology , Rats , Structure-Activity Relationship , Thiazines/pharmacokinetics , Thiazines/pharmacology
4.
PLoS One ; 12(12): e0189060, 2017.
Article in English | MEDLINE | ID: mdl-29206860

ABSTRACT

The mechanism behind the glucose lowering effect occurring after specific activation of GPR120 is not completely understood. In this study, a potent and selective GPR120 agonist was developed and its pharmacological properties were compared with the previously described GPR120 agonist Metabolex-36. Effects of both compounds on signaling pathways and GLP-1 secretion were investigated in vitro. The acute glucose lowering effect was studied in lean wild-type and GPR120 null mice following oral or intravenous glucose tolerance tests. In vitro, in GPR120 overexpressing cells, both agonists signaled through Gαq, Gαs and the ß-arrestin pathway. However, in mouse islets the signaling pathway was different since the agonists reduced cAMP production. The GPR120 agonists stimulated GLP-1 secretion both in vitro in STC-1 cells and in vivo following oral administration. In vivo GPR120 activation induced significant glucose lowering and increased insulin secretion after intravenous glucose administration in lean mice, while the agonists had no effect in GPR120 null mice. Exendin 9-39, a GLP-1 receptor antagonist, abolished the GPR120 induced effects on glucose and insulin following an intravenous glucose challenge. In conclusion, GLP-1 secretion is an important mechanism behind the acute glucose lowering effect following specific GPR120 activation.


Subject(s)
Blood Glucose/metabolism , Glucagon-Like Peptide 1/pharmacology , Receptors, G-Protein-Coupled/agonists , Animals , CHO Cells , Cell Line , Cricetulus , Cyclic AMP/biosynthesis , Female , GTP-Binding Proteins/metabolism , Glucose Tolerance Test , Humans , Insulin/metabolism , Insulin Secretion , Islets of Langerhans/drug effects , Islets of Langerhans/metabolism , Mice , Mice, Inbred C57BL , Signal Transduction , beta-Arrestins/metabolism
5.
J Med Chem ; 60(24): 10071-10091, 2017 12 28.
Article in English | MEDLINE | ID: mdl-29172502

ABSTRACT

Herein we report the optimization of a series of pyrrolopyrimidine inhibitors of interleukin-1 receptor associated kinase 4 (IRAK4) using X-ray crystal structures and structure based design to identify and optimize our scaffold. Compound 28 demonstrated a favorable physicochemical and kinase selectivity profile and was identified as a promising in vivo tool with which to explore the role of IRAK4 inhibition in the treatment of mutant MYD88L265P diffuse large B-cell lymphoma (DLBCL). Compound 28 was shown to be capable of demonstrating inhibition of NF-κB activation and growth of the ABC subtype of DLBCL cell lines in vitro at high concentrations but showed greater effects in combination with a BTK inhibitor at lower concentrations. In vivo, the combination of compound 28 and ibrutinib led to tumor regression in an ABC-DLBCL mouse model.


Subject(s)
Antineoplastic Agents/pharmacology , Interleukin-1 Receptor-Associated Kinases/antagonists & inhibitors , Lymphoma, Large B-Cell, Diffuse/drug therapy , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Administration, Oral , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacokinetics , Cell Line, Tumor , Crystallography, X-Ray , Dogs , Female , Humans , Interleukin-1 Receptor-Associated Kinases/chemistry , Lymphoma, Large B-Cell, Diffuse/genetics , Magnetic Resonance Spectroscopy , Male , Mice, SCID , Mutation , Myeloid Differentiation Factor 88/genetics , Protein Kinase Inhibitors/administration & dosage , Pyrimidines/chemistry , Pyrroles/chemistry , Rats, Wistar , Structure-Activity Relationship , Xenograft Model Antitumor Assays
6.
J Med Chem ; 57(3): 970-86, 2014 Feb 13.
Article in English | MEDLINE | ID: mdl-24422550

ABSTRACT

11ß-Hydroxysteroid dehydrogenase type 1 (11ß-HSD1) has been widely considered by the pharmaceutical industry as a target to treat metabolic syndrome in type II diabetics. We hypothesized that central nervous system (CNS) penetration might be required to see efficacy. Starting from a previously reported pyrimidine compound, we removed hydrogen-bond donors to yield 3, which had modest CNS penetration. More significant progress was achieved by changing the core to give 40, which combines good potency and CNS penetration. Compound 40 was dosed to diet-induced obese (DIO) mice and gave excellent target engagement in the liver and high free exposures of drug, both peripherally and in the CNS. However, no body weight reduction or effects on glucose or insulin were observed in this model. Similar data were obtained with a structurally diverse thiazole compound 51. This work casts doubt on the hypothesis that localized tissue modulation of 11ß-HSD1 activity alleviates metabolic syndrome.


Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1/antagonists & inhibitors , Adamantane/analogs & derivatives , Adamantane/chemical synthesis , Brain/metabolism , Diabetes Mellitus, Type 2/drug therapy , Hypoglycemic Agents/chemical synthesis , Metabolic Syndrome/drug therapy , 11-beta-Hydroxysteroid Dehydrogenase Type 1/chemistry , Adamantane/pharmacokinetics , Adamantane/pharmacology , Animals , Blood Glucose/metabolism , Body Weight/drug effects , Crystallography, X-Ray , Cyclopropanes/chemical synthesis , Cyclopropanes/pharmacokinetics , Cyclopropanes/pharmacology , Diabetes Mellitus, Type 2/metabolism , Diabetes Mellitus, Type 2/physiopathology , Dietary Fats/administration & dosage , Humans , Hypoglycemic Agents/pharmacokinetics , Hypoglycemic Agents/pharmacology , Insulin/blood , Isoenzymes/antagonists & inhibitors , Isoenzymes/chemistry , Liver/drug effects , Liver/metabolism , Male , Metabolic Syndrome/metabolism , Metabolic Syndrome/physiopathology , Mice , Mice, Inbred C57BL , Mice, Obese , Models, Molecular , Pyrazoles/chemical synthesis , Pyrazoles/pharmacokinetics , Pyrazoles/pharmacology , Rats , Stereoisomerism , Structure-Activity Relationship , Thiazoles/chemical synthesis , Thiazoles/pharmacokinetics , Thiazoles/pharmacology
7.
Bioorg Med Chem Lett ; 23(11): 3175-9, 2013 Jun 01.
Article in English | MEDLINE | ID: mdl-23628336

ABSTRACT

A series of conformationally restricted GPR119 agonists were prepared based around a 3,8-diazabicyclo[3.2.1]octane scaffold. Examples were found to have markedly different pharmacology in mouse and human despite similar levels of binding to the receptor. This highlights the large effects on GPCR phamacology that can result from small structural changes in the ligand, together with inter-species differences between receptors.


Subject(s)
Bridged Bicyclo Compounds, Heterocyclic/chemistry , Heterocyclic Compounds, 2-Ring/chemistry , Pyrimidines/chemistry , Receptors, G-Protein-Coupled/agonists , Animals , Biological Availability , Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , Bridged Bicyclo Compounds, Heterocyclic/pharmacokinetics , Cell Membrane Permeability/drug effects , Cyclic AMP/metabolism , Dogs , Half-Life , Heterocyclic Compounds, 2-Ring/chemical synthesis , Heterocyclic Compounds, 2-Ring/pharmacokinetics , Humans , Madin Darby Canine Kidney Cells , Mice , Protein Binding , Pyrimidines/chemical synthesis , Pyrimidines/pharmacokinetics , Receptors, G-Protein-Coupled/metabolism , Structure-Activity Relationship
8.
J Med Chem ; 55(23): 10652-61, 2012 Dec 13.
Article in English | MEDLINE | ID: mdl-23153367

ABSTRACT

11ß-Hydroxysteroid dehydrogenase 1 (11ß-HSD1) has been a target of intensive research efforts across the pharmaceutical industry, due to its potential for the treatment of type II diabetes and other elements of the metabolic syndrome. To demonstrate the value of 11ß-HSD1 in preclinical models, we required inhibitors with good potency against both human and rodent isoforms. Herein, we describe our efforts to understand how to co-optimize human and murine potency within the (5-hydroxy-2-adamantyl)-pyrimidine-5-carboxamide series. Two approaches are described-a data-driven (Free-Wilson) analysis and a structure-based design approach. The conclusions from these approaches were used to inform an efficient campaign to design compounds with consistently good human/murine potency within a logD(7.4) range of 1-3. Compounds 20 and 26 demonstrated good rodent PK, which allowed us to demonstrate a PK/PD relationship in rat and mouse. We then evaluated 26 against glycemic and body weight end points in murine disease models, where it demonstrated glucose and body weight efficacy at 300 mg/kg/day but only body weight efficacy at 50 mg/kg/day, despite providing >90% target engagement in the liver.


Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1/antagonists & inhibitors , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Isoenzymes/antagonists & inhibitors , 11-beta-Hydroxysteroid Dehydrogenase Type 1/chemistry , Animals , Enzyme Inhibitors/pharmacokinetics , Humans , Inhibitory Concentration 50 , Isoenzymes/chemistry , Magnetic Resonance Spectroscopy , Mice , Models, Molecular
9.
Bioorg Med Chem Lett ; 22(21): 6756-61, 2012 Nov 01.
Article in English | MEDLINE | ID: mdl-23013933

ABSTRACT

11ß-HSD1 is increasingly seen as an attractive target for the treatment of type II diabetes and other elements of the metabolic syndrome. In this program of work we describe how a series of neutral 2-thioalkyl-pyridine 11ß-HSD1 inhibitors were optimized in terms of their pharmacokinetic properties to give compounds with excellent bioavailability in both rat and dog through a core change to pyrimidine. A potential reactive metabolite issue with 4-thioalkyl-pyrimidines was circumvented by a switch from sulfur to carbon substitution.


Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1/antagonists & inhibitors , Enzyme Inhibitors/pharmacokinetics , Pyridines/chemistry , Sulfhydryl Compounds/chemistry , Animals , Dogs , Enzyme Inhibitors/chemistry , Inhibitory Concentration 50 , Molecular Structure , Pyridines/pharmacokinetics , Rats , Sulfhydryl Compounds/pharmacokinetics
10.
J Med Chem ; 55(11): 5361-79, 2012 Jun 14.
Article in English | MEDLINE | ID: mdl-22545772

ABSTRACT

G protein coupled receptor 119 (GPR119) is viewed as an attractive target for the treatment of type 2 diabetes and other elements of the metabolic syndrome. During a program toward discovering agonists of GPR119, we herein describe optimization of an initial lead compound, 2, into a development candidate, 42. A key challenge in this program of work was the insolubility of the lead compound. Small-molecule crystallography was utilized to understand the intermolecular interactions in the solid state and resulted in a switch from an aryl sulphone to a 3-cyanopyridyl motif. The compound was shown to be effective in wild-type but not knockout animals, confirming that the biological effects were due to GPR119 agonism.


Subject(s)
Oxadiazoles/chemical synthesis , Pyridines/chemical synthesis , Receptors, G-Protein-Coupled/agonists , Animals , Biological Availability , Carbamates/chemical synthesis , Carbamates/chemistry , Carbamates/pharmacology , Crystallography, X-Ray , Dogs , High-Throughput Screening Assays , Humans , Mice , Mice, Inbred C57BL , Mice, Knockout , Models, Molecular , Molecular Structure , Oxadiazoles/chemistry , Oxadiazoles/pharmacology , Piperidines/chemical synthesis , Piperidines/chemistry , Piperidines/pharmacology , Pyridines/chemistry , Pyridines/pharmacology , Rats , Rats, Wistar , Receptors, G-Protein-Coupled/chemistry , Receptors, G-Protein-Coupled/metabolism , Small Molecule Libraries , Solubility , Stereoisomerism , Structure-Activity Relationship , Sulfones/chemical synthesis , Sulfones/chemistry , Sulfones/pharmacology
11.
Bioorg Med Chem Lett ; 21(24): 7310-6, 2011 Dec 15.
Article in English | MEDLINE | ID: mdl-22061639

ABSTRACT

GPR119 is increasingly seen as an attractive target for the treatment of type II diabetes and other elements of the metabolic syndrome. During a programme aimed at developing agonists of the GPR119 receptor, we identified compounds that were potent with reduced hERG liabilities, that had good pharmacokinetic properties and that displayed excellent glucose-lowering effects in vivo. However, further profiling in a GPR119 knock-out (KO) mouse model revealed that the biological effects were not exclusively due to GPR119 agonism, highlighting the value of transgenic animals in drug discovery programs.


Subject(s)
Hypoglycemic Agents/chemistry , Receptors, G-Protein-Coupled/agonists , Administration, Oral , Animals , Diabetes Mellitus, Experimental/drug therapy , Drug Evaluation, Preclinical , ERG1 Potassium Channel , Ether-A-Go-Go Potassium Channels/metabolism , Humans , Hypoglycemic Agents/pharmacokinetics , Hypoglycemic Agents/therapeutic use , Mice , Mice, Inbred C57BL , Mice, Knockout , Receptors, G-Protein-Coupled/deficiency , Receptors, G-Protein-Coupled/genetics , Receptors, G-Protein-Coupled/metabolism , Structure-Activity Relationship
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