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1.
Bioorg Med Chem ; 28(1): 115232, 2020 01 01.
Article in English | MEDLINE | ID: mdl-31818630

ABSTRACT

Glucose flux through glucokinase (GK) controls insulin release from the pancreas in response to high levels of glucose. Flux through GK is also responsible for reducing hepatic glucose output. Since many individuals with type 2 diabetes appear to have an inadequacy or defect in one or both of these processes, identifying compounds that can activate GK could provide a therapeutic benefit. Herein we report the further structure activity studies of a novel series of glucokinase activators (GKA). These studies led to the identification of pyridine 72 as a potent GKA that lowered post-prandial glucose in normal C57BL/6J mice, and after 14d dosing in ob/ob mice.


Subject(s)
Enzyme Activators/chemistry , Glucokinase/chemistry , Hypoglycemic Agents/chemistry , Animals , Binding Sites , Blood Glucose/analysis , Crystallography, X-Ray , Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Experimental/pathology , Drug Design , Drug Evaluation, Preclinical , Enzyme Activators/metabolism , Enzyme Activators/therapeutic use , Glucokinase/metabolism , Glucose Tolerance Test , Hypoglycemic Agents/metabolism , Hypoglycemic Agents/therapeutic use , Kinetics , Mice , Mice, Inbred C57BL , Molecular Dynamics Simulation , Structure-Activity Relationship , Thiadiazoles/chemistry , Thiadiazoles/metabolism
2.
ACS Med Chem Lett ; 7(7): 714-8, 2016 Jul 14.
Article in English | MEDLINE | ID: mdl-27437083

ABSTRACT

Glucokinase (GK) catalyzes the phosphorylation of glucose to glucose-6-phosphate. We present the structure-activity relationships leading to the discovery of AM-2394, a structurally distinct GKA. AM-2394 activates GK with an EC50 of 60 nM, increases the affinity of GK for glucose by approximately 10-fold, exhibits moderate clearance and good oral bioavailability in multiple animal models, and lowers glucose excursion following an oral glucose tolerance test in an ob/ob mouse model of diabetes.

3.
ACS Med Chem Lett ; 5(12): 1284-9, 2014 Dec 11.
Article in English | MEDLINE | ID: mdl-25516785

ABSTRACT

Glucokinase (GK) activators represent a class of type 2 diabetes therapeutics actively pursued due to the central role that GK plays in regulating glucose homeostasis. Herein we report a novel C5-alkyl-2-methylurea-substituted pyridine series of GK activators derived from our previously reported thiazolylamino pyridine series. Our efforts in optimizing potency, enzyme kinetic properties, and metabolic stability led to the identification of compound 26 (AM-9514). This analogue showed a favorable combination of in vitro potency, enzyme kinetic properties, acceptable pharmacokinetic profiles in preclinical species, and robust efficacy in a rodent PD model.

4.
J Med Chem ; 57(19): 8180-6, 2014 Oct 09.
Article in English | MEDLINE | ID: mdl-25203462

ABSTRACT

Glucokinase (GK) is the rate-limiting step for insulin release from the pancreas in response to high levels of glucose. Flux through GK also contributes to reducing hepatic glucose output. Since many individuals with type 2 diabetes appear to have an inadequacy or defect in one or both of these processes, identifying compounds that can allosterically activate GK may address this issue. Herein we report the identification and initial optimization of a novel series of glucokinase activators (GKAs). Optimization led to the identification of 33 as a compound that displayed activity in an oral glucose tolerance test (OGTT) in normal and diabetic mice.


Subject(s)
Enzyme Activators/chemical synthesis , Glucokinase/metabolism , Pyridines/chemical synthesis , Urea/analogs & derivatives , Animals , Drug Discovery , Enzyme Activators/pharmacology , Glucose Tolerance Test , Mice, Inbred C57BL , Pyridines/pharmacology
5.
Bioorg Med Chem ; 22(19): 5428-45, 2014 Oct 01.
Article in English | MEDLINE | ID: mdl-25187277

ABSTRACT

In the course of our study on selective nonsteroidal mineralocorticoid receptor (MR) antagonists, a series of novel benzoxazine derivatives possessing an azole ring as the core scaffold was designed for the purpose of attenuating the partial agonistic activity of the previously reported dihydropyrrol-2-one derivatives. Screening of alternative azole rings identified 1,3-dimethyl pyrazole 6a as a lead compound with reduced partial agonistic activity. Subsequent replacement of the 1-methyl group of the pyrazole ring with larger lipophilic side chains or polar side chains targeting Arg817 and Gln776 increased MR binding activity while maintaining the agonistic response at the lower level. Among these compounds, 6-[1-(2,2-difluoro-3-hydroxypropyl)-5-(4-fluorophenyl)-3-methyl-1H-pyrazol-4-yl]-2H-1,4-benzoxazin-3(4H)-one (37a) showed highly potent in vitro activity, high selectivity versus other steroid hormone receptors, and good pharmacokinetic profiles. Oral administration of 37a in deoxycorticosterone acetate-salt hypertensive rats showed a significant blood pressure-lowering effect with no signs of antiandrogenic effects.


Subject(s)
Drug Discovery , Mineralocorticoid Receptor Antagonists/pharmacology , Oxazines/pharmacology , Pyrazoles/pharmacology , Receptors, Mineralocorticoid/metabolism , Androgen Antagonists/administration & dosage , Androgen Antagonists/chemistry , Androgen Antagonists/pharmacology , Animals , Antihypertensive Agents/administration & dosage , Antihypertensive Agents/chemistry , Antihypertensive Agents/pharmacology , COS Cells , Chlorocebus aethiops , Crystallography, X-Ray , Desoxycorticosterone Acetate , Dose-Response Relationship, Drug , Humans , Hypertension/chemically induced , Hypertension/drug therapy , Male , Mineralocorticoid Receptor Antagonists/administration & dosage , Mineralocorticoid Receptor Antagonists/chemistry , Models, Molecular , Molecular Structure , Oxazines/administration & dosage , Oxazines/chemistry , Pyrazoles/administration & dosage , Pyrazoles/chemistry , Rats , Rats, Wistar , Receptors, Mineralocorticoid/agonists , Structure-Activity Relationship
6.
J Med Chem ; 56(19): 7669-78, 2013 Oct 10.
Article in English | MEDLINE | ID: mdl-24015910

ABSTRACT

Glucose flux through glucokinase (GK) controls insulin release from the pancreas in response to high glucose concentrations. Glucose flux through GK also contributes to reducing hepatic glucose output. Because many individuals with type 2 diabetes appear to have an inadequacy or defect in one or both of these processes, compounds that can activate GK may serve as effective treatments for type 2 diabetes. Herein we report the identification and initial optimization of a novel series of allosteric glucokinase activators (GKAs). We discovered an initial thiazolylamino pyridine-based hit that was optimized using a structure-based design strategy and identified 26 as an early lead. Compound 26 demonstrated a good balance of in vitro potency and enzyme kinetic parameters and demonstrated blood glucose reductions in oral glucose tolerance tests in both C57BL/6J mice and high-fat fed Zucker diabetic fatty rats.


Subject(s)
Aminopyridines/chemical synthesis , Enzyme Activators/chemical synthesis , Glucokinase/metabolism , Hypoglycemic Agents/chemical synthesis , Thiazoles/chemical synthesis , Allosteric Regulation , Aminopyridines/chemistry , Aminopyridines/pharmacology , Animals , Diabetes Mellitus, Type 2/drug therapy , Enzyme Activators/chemistry , Enzyme Activators/pharmacology , Glucose Tolerance Test , Humans , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacology , Mice , Mice, Inbred C57BL , Rats , Rats, Zucker , Structure-Activity Relationship , Thiazoles/chemistry , Thiazoles/pharmacology , Young Adult
7.
Bioorg Med Chem ; 21(19): 5983-94, 2013 Oct 01.
Article in English | MEDLINE | ID: mdl-23958516

ABSTRACT

Dihydrofuran-2-one and dihydropyrrol-2-one derivatives were identified as novel, potent and selective mineralocorticoid receptor (MR) antagonists by the structure-based drug design approach utilizing the crystal structure of MR/compound complex. Introduction of lipophilic substituents directed toward the unfilled spaces of the MR and identification of a new scaffold, dihydropyrrol-2-one ring, led to potent in vitro activity. Among the synthesized compounds, dihydropyrrol-2-one 11i showed an excellent in vitro activity (MR binding IC50=43nM) and high selectivity over closely related steroid receptors such as the androgen receptor (AR), progesterone receptor (PR) and glucocorticoid receptor (GR) (>200-fold for AR and PR, 100-fold for GR).


Subject(s)
Benzofurans/chemistry , Benzoxazines/chemistry , Drug Design , Mineralocorticoid Receptor Antagonists/chemical synthesis , Pyrroles/chemistry , Animals , COS Cells , Chlorocebus aethiops , Crystallography, X-Ray , Inhibitory Concentration 50 , Mineralocorticoid Receptor Antagonists/chemistry , Mineralocorticoid Receptor Antagonists/pharmacology , Protein Binding/drug effects , Structure-Activity Relationship
8.
J Med Chem ; 54(24): 8616-31, 2011 Dec 22.
Article in English | MEDLINE | ID: mdl-22074142

ABSTRACT

Mineralocorticoid receptor (MR) blockade has come into focus as a promising approach for the treatment of cardiovascular diseases such as hypertension and congestive heart failure. In order to identify a novel class of nonsteroidal MR antagonists that exhibit significant potency and good selectivity over other steroidal hormone receptors, we designed a novel series of benzoxazin-3-one derivatives and synthesized them from 6-(7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-6-yl)-2H-1,4-benzoxazin-3(4H)-one (1a), high-throughput screening (HTS) hit compound. Our design was based on a crystal structure of an MR/compound complex and a docking model. In the course of lead generation from 1a, a 1,2-diaryl framework was characterized as a key structure with high binding affinity. On the basis of scaffold hopping and optimization studies, benzoxazin-3-one derivatives possessing 1-phenyl-3-trifluoromethylpyrazol-5-yl moiety at the 6-position were identified as a novel series of potent and selective MR antagonists. Among these compounds, 6-[1-(4-fluoro-2-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-2H-1,4-benzoxazin-3(4H)-one (14n) showed highly potent activity and good selectivity and also exhibited a significant antihypertensive effect in deoxycorticosterone acetate-salt hypertensive rats. On the basis of these results, compound 14n was progressed for further pharmacological evaluation.


Subject(s)
Antihypertensive Agents/chemical synthesis , Benzoxazines/chemical synthesis , Mineralocorticoid Receptor Antagonists , Pyrazoles/chemical synthesis , Animals , Antihypertensive Agents/pharmacokinetics , Antihypertensive Agents/pharmacology , Benzoxazines/pharmacokinetics , Benzoxazines/pharmacology , Binding, Competitive , Crystallography, X-Ray , Microsomes, Liver/metabolism , Models, Molecular , Protein Conformation , Pyrazoles/pharmacokinetics , Pyrazoles/pharmacology , Rats , Rats, Wistar , Structure-Activity Relationship
9.
Expert Rev Clin Pharmacol ; 3(2): 209-29, 2010 Mar.
Article in English | MEDLINE | ID: mdl-22111568

ABSTRACT

The microvascular complications of insufficiently controlled diabetes (neuropathy, retinopathy and nephropathy) and the marked increased risk of macrovascular events (e.g., stroke and myocardial infarction) have a dire impact on society in both human and economic terms. In Type 1 diabetes total ß-cell loss occurs. In Type 2 diabetes, partial ß-cell loss occurs before diagnosis, and the progressive ß-cell loss during the life of the patient increases the severity of the disease. In patients with diabetes, increased insulin resistance in the muscle and liver are key pathophysiologic defects. In addition, defects in metabolic processes in the fat, GI tract, brain, pancreatic α-cells and kidney are detrimental to the overall health of the patient. This review addresses novel therapies for these deficiencies in clinical and preclinical evaluation, emphasizing their potential to address glucose homeostasis, ß-cell mass and function, and the comorbidities of cardiovascular disease and obesity.

10.
Bioorg Med Chem Lett ; 18(6): 2206-10, 2008 Mar 15.
Article in English | MEDLINE | ID: mdl-18267359

ABSTRACT

Tumor cells extensively utilize the pentose phosphate pathway for the synthesis of ribose. Transketolase is a key enzyme in this pathway and has been suggested as a target for inhibition in the treatment of cancer. In a pharmacodynamic study, nude mice with xenografted HCT-116 tumors were dosed with 1 ('N3'-pyridyl thiamine'; 3-(6-methyl-2-amino-pyridin-3-ylmethyl)-5-(2-hydroxy-ethyl)-4-methyl-thiazol-3-ium chloride hydrochloride), an analog of thiamine, the co-factor of transketolase. Transketolase activity was almost completely suppressed in blood, spleen, and tumor cells, but there was little effect on the activity of the other thiamine-utilizing enzymes alpha-ketoglutarate dehydrogenase or glucose-6-phosphate dehydrogenase. Synthesis and SAR of transketolase inhibitors is described.


Subject(s)
Colonic Neoplasms/drug therapy , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Thiamine/analogs & derivatives , Thiamine/antagonists & inhibitors , Transketolase/antagonists & inhibitors , Animals , Colonic Neoplasms/enzymology , Crystallography, X-Ray , Glucosephosphate Dehydrogenase/metabolism , Humans , In Vitro Techniques , Ketoglutarate Dehydrogenase Complex/metabolism , Magnetic Resonance Spectroscopy , Mice , Mice, Nude , Molecular Structure , Oxythiamine/antagonists & inhibitors , Phosphorylation/drug effects , Spleen/drug effects , Spleen/enzymology , Structure-Activity Relationship , Xenograft Model Antitumor Assays
11.
Bioorg Med Chem Lett ; 18(2): 509-12, 2008 Jan 15.
Article in English | MEDLINE | ID: mdl-18182286

ABSTRACT

Inhibition of the thiamine-utilizing enzyme transketolase (TK) has been linked with diminished tumor cell proliferation. Most thiamine antagonists have a permanent positive charge on the B-ring, and it has been suggested that this charge is required for diphosphorylation by thiamine pyrophosphokinase (TPPK) and binding to TK. We sought to make neutral thiazolium replacements that would be substrates for TPPK, while not necessarily needing thiamine transporters (ThTr1 and ThTr2) for cell penetration. The synthesis, SAR, and structure-based rationale for highly potent non-thiazolium TK antagonists are presented.


Subject(s)
Enzyme Inhibitors/pharmacology , Thiamine/analogs & derivatives , Transketolase/antagonists & inhibitors , Animals , Catalysis , Cell Line , Crystallography, X-Ray , Enzyme Inhibitors/chemistry , Humans , Mice , Protein Conformation , Structure-Activity Relationship , Thiamine/chemistry , Thiamine/pharmacology
12.
Bioorg Med Chem Lett ; 18(2): 505-8, 2008 Jan 15.
Article in English | MEDLINE | ID: mdl-18083562

ABSTRACT

Transketolase, a key enzyme in the pentose phosphate pathway, has been suggested as a target for inhibition in the treatment of cancer. Compound 5a ('N3'-pyridyl thiamine'; 3-(6-methyl-2-amino-pyridin-3-ylmethyl)-5-(2-hydroxy-ethyl)-4-methyl-thiazol-3-ium chloride hydrochloride), an analog of the transketolase cofactor thiamine, is a potent transketolase inhibitor but suffers from poor pharmacokinetics due to high clearance and C(max) linked toxicity. An efficient way of improving the pharmacokinetic profile of 5a is to prepare oxidized prodrugs which are slowly reduced in vivo yielding longer, sustained blood levels of the drug. The synthesis of such prodrugs and their evaluation in rodent models is reported.


Subject(s)
Enzyme Inhibitors/pharmacology , Prodrugs/pharmacology , Thiamine/analogs & derivatives , Transketolase/antagonists & inhibitors , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacokinetics , Molecular Structure , Prodrugs/chemistry , Prodrugs/pharmacokinetics , Thiamine/chemistry , Thiamine/pharmacokinetics , Thiamine/pharmacology
13.
Environ Health Perspect ; 113(2): 180-5, 2005 Feb.
Article in English | MEDLINE | ID: mdl-15687055

ABSTRACT

The effectiveness of bioremediation efforts is assessed traditionally from the loss of the chemical of interest. In some cases, analytical techniques are coupled with evaluation of toxicity to organisms representative of those found in the affected environment or surrogate organisms. Little is known, however, about the effect of remediation of environmental chemicals on potential toxicity to mammalian organisms. We discuss both an approach that employs mammalian cell system bioassays and the criteria for selection of the assays. This approach has been used to evaluate the biological response to mixtures of polychlorinated biphenyls (PCBs) before and after remediation by reductive dechlorination. The dechlorination process used results in accumulation of congeners substituted in only the ortho and para positions and containing fewer chlorines than the starting mixtures. Evaluation of the dechlorinated mixture reveals a loss of biological activity that could be ascribed to coplanar PCBs not containing chlorine in the ortho positions. Conversely, biological activity associated with ortho-substituted PCB congeners is unaffected or increased by remediation. Thus, the results of the bioassays are consistent with the remediation-induced change in the profile of PCB congeners and the known mechanisms of action of PCBs. The results emphasize a need for evaluation of the products of remediation for biological activity in mammalian systems. Furthermore, the approach outlined demonstrates the potential to assess the impact of remediation on a range of biological activities in mammalian cells and thus to estimate positive and negative effects of remediation strategies on toxicity. Future needs in this area of research include assays to evaluate biological effects under conditions of exposure that mimic those found in the environment and models to extrapolate effects to assess risk to people and wildlife.


Subject(s)
Chlorine/chemistry , Polychlorinated Biphenyls/metabolism , Soil Pollutants/metabolism , Animals , Biodegradation, Environmental , Biological Assay/methods , Biotransformation , Evaluation Studies as Topic , Oxidation-Reduction , Polychlorinated Biphenyls/toxicity , Soil Pollutants/toxicity
14.
J Org Chem ; 67(3): 943-8, 2002 Feb 08.
Article in English | MEDLINE | ID: mdl-11856042

ABSTRACT

A series of thieno[2,3-c]pyridine antagonists of cell adhesion molecule (CAM) expression, such as A-205804 (1) and A-249377 (2), selectively suppressed the induced expression of E-selectin and ICAM-1 over VCAM-1. In an effort to explore the biological mechanism of action of these inhibitors, we synthesized (125)I- and (3)H-labeled thieno[2,3-c]pyridines 5 and 6. An isolated diazonium tetrafluoroborate salt efficiently trapped Na(125)I on very small scale (7.5 microg of Na(125)I), providing the corresponding (125)I-labeled thieno[2,3-c]pyridine in modest yield. Preliminary mechanistic investigations using these radiolabeled compounds revealed that, upon incubation with human umbilical vein endothelial cells (HUVECs), these inhibitors of CAM expression translocated to the cell nucleus and were noncovalently associated with macromolecules of molecular weight greater than 650 kDa.


Subject(s)
Cell Adhesion Molecules/antagonists & inhibitors , Pyridines/chemical synthesis , Pyridines/pharmacology , Cell Adhesion Molecules/metabolism , Cells, Cultured , Chromatography, Gel , Humans , Iodine Radioisotopes , Magnetic Resonance Spectroscopy , Mass Spectrometry , Pyridines/chemistry , Tritium
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