A5061899195- Biochemical Acid Research Studies
- Pancreatic function and diabetes
- Biochemical and Molecular Research
- Metabolism, Diabetes, and Cancer
- Metabolism and Genetic Disorders
- Cancer Immunotherapy and Biomarkers
- Asymmetric Synthesis and Catalysis
- Diabetes Treatment and Management
- Coordination Chemistry and Organometallics
- Cytokine Signaling Pathways and Interactions
- Immune cells in cancer
- Psoriasis: Treatment and Pathogenesis
- T-cell and B-cell Immunology
- Carbohydrate Chemistry and Synthesis
- ATP Synthase and ATPases Research
- Diabetes Management and Research
- Immunotherapy and Immune Responses
- Synthesis and pharmacology of benzodiazepine derivatives
- Cancer, Hypoxia, and Metabolism
- Microbial Natural Products and Biosynthesis
- Cyclopropane Reaction Mechanisms
- Immune Cell Function and Interaction
- Chemical synthesis and alkaloids
- Lipid metabolism and biosynthesis
- Cardiovascular, Neuropeptides, and Oxidative Stress Research
Lycera (United States)
2014-2024
Array BioPharma (United States)
2005-2019
Novartis (United States)
1999-2000
Novartis (Switzerland)
1998-2000
Harvard University
1987-1992
Marquette University
1984
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTTotal synthesis of halichondrin B and norhalichondrin BThomas D. Aicher, Keith R. Buszek, Francis G. Fang, Craig J. Forsyth, Sun Ho Jung, Yoshito Kishi, Michael C. Matelich, Paul M. Scola, Denice Spero, Suk Kyoon YoonCite this: Am. Chem. Soc. 1992, 114, 8, 3162–3164Publication Date (Print):April 1, 1992Publication History Published online1 May 2002Published inissue 1 April...
RORγt is the key transcription factor controlling development and function of CD4+ Th17 CD8+ Tc17 cells. Across a range human tumors, about 15% T cell fraction in tumor-infiltrating lymphocytes are RORγ+ To evaluate role RORγ antitumor immunity, we have identified synthetic, small molecule agonists that selectively activate to greater extent than endogenous agonist desmosterol. These enhance effector Type 17 cells by increasing production cytokines/chemokines such as IL-17A GM-CSF,...
A series of activators GCN2 (general control nonderepressible 2) kinase have been developed, leading to HC-7366, which has entered the clinic as an antitumor therapy. Optimization resulted in improved permeability compared that original indazole hinge binding scaffold, while maintaining potency at and selectivity over PERK (protein RNA-like endoplasmic reticulum kinase). The ADME properties this led robust vivo compound exposure both rats mice, allowing HC-7366 be dosed xenograft models,...
Recent studies have elucidated the molecular mechanism of RORγT transcriptional regulation Th17 differentiation and function. was initially identified as a transcription factor required for thymopoiesis by maintaining survival CD4+CD8+ (DP) thymocytes. While RORγ antagonists are currently being developed to treat autoimmunity, it remains unclear how inhibition may impact thymocyte development. In this study, we show that in addition regulating DP thymocytes survival, also controls genes...
N'-methyl-N-(4-tert-butyl-1,2,5,6-tetrahydropyridine)thiourea, SDZ048-619 (1), is a modest inhibitor (IC(50) = 180 microM) of pyruvate dehydrogenase kinase (PDHK). In an optimization the N-methylcarbothioamide moiety 1, it was discovered that amides with small acyl group, in particular appropriately substituted (R)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid, are inhibitors PDHK. Utilizing this moiety, herein reported rationale leading to series acylated piperazine derivatives. Methyl...
A series of substituted tetrahydropyrrolo[2,1-b]oxazol-5(6H)-ones and tetrahydropyrrolo[2,1-b]thiazol-5(6H)-ones was synthesized from amino alcohols or thiols keto acids. pharmacological model based on the results obtained with these compounds led to synthesis evaluation a isoxazoles other monocyclic compounds. These were evaluated for their ability enhance glucose utilization in cultured L6 myocytes. The vivo hypoglycemic efficacy potency type 2 diabetes mellitus (non-insulin-dependent...
The optimization of a series anilide derivatives (R)-3,3, 3-trifluoro-2-hydroxy-2-methylpropionic acid as inhibitors pyruvate dehydrogenase kinase (PDHK) is described that started from N-phenyl-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide 1 (IC(50) = 35 +/- 1.4 microM). It was found small electron-withdrawing groups on the ortho position anilide, i.e., chloro, acetyl, or bromo, increased potency 20-40-fold. oral bioavailability compounds in this optimal (as measured by AUC) when substituted...
Glucose flux through glucokinase (GK) controls insulin release from the pancreas in response to high glucose concentrations. GK also contributes reducing hepatic output. Because many individuals with type 2 diabetes appear have an inadequacy or defect one both of these processes, compounds that can activate may serve as effective treatments for diabetes. Herein we report identification and initial optimization a novel series allosteric activators (GKAs). We discovered thiazolylamino...
Retinoic acid receptor-related orphan receptor γ (RORc, RORγ, or NR1F3) is the nuclear master transcription factor that drives function and development of IL-17-producing T helper cells (Th17), cytotoxic (Tc17), subsets innate lymphoid cells. Activation RORγ
High-throughput screening identified 5 as a weak inhibitor of 11β-HSD1. Optimization the structure led to series perhydroquinolylbenzamides, some with low nanomolar inhibitory potency. A tertiary benzamide is required for biological activity and substitution terminal either electron-donating or -withdrawing groups tolerated. The majority compounds show selectivity >20 >700-fold over 11β-HSD2. Analogues which showed >50% inhibition 11β-HSD1 at 1 μM in an cellular assay were screened ADX mouse...
ADVERTISEMENT RETURN TO ISSUEPREVLetterNEXT(R)-3,3,3-Trifluoro-2-hydroxy-2-methylpropionamides Are Orally Active Inhibitors of Pyruvate Dehydrogenase KinaseThomas D. Aicher, Robert C. Anderson, Gregory R. Bebernitz, Gary M. Coppola, Charles F. Jewell, Douglas Knorr, Liu, Donald Sperbeck, Leonard J. Brand, Strohschein, Jiaping Gao, Christine Vinluan, Suraj S. Shetty, Carol Dragland, Emma L. Kaplan, Dominick DelGrande, Amin Islam, Xilin Lozito, Wieslawa Maniara, Erik Walter, and William...
The microvascular complications of insufficiently controlled diabetes (neuropathy, retinopathy and nephropathy) the marked increased risk macrovascular events (e.g., stroke myocardial infarction) have a dire impact on society in both human economic terms. In Type 1 total β-cell loss occurs. 2 diabetes, partial occurs before diagnosis, progressive during life patient increases severity disease. patients with insulin resistance muscle liver are key pathophysiologic defects. addition, defects...
Glucokinase (GK) is the rate-limiting step for insulin release from pancreas in response to high levels of glucose. Flux through GK also contributes reducing hepatic glucose output. Since many individuals with type 2 diabetes appear have an inadequacy or defect one both these processes, identifying compounds that can allosterically activate may address this issue. Herein we report identification and initial optimization a novel series glucokinase activators (GKAs). Optimization led 33 as...
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 novel C5-alkyl-2-methylurea-substituted pyridine series derived from our previously reported thiazolylamino series. Our efforts optimizing potency, enzyme kinetic properties, and metabolic stability led identification compound 26 (AM-9514). This analogue showed favorable combination vitro acceptable...
Glucokinase (GK) catalyzes the phosphorylation of glucose to glucose-6-phosphate. We present structure-activity relationships leading discovery AM-2394, a structurally distinct GKA. AM-2394 activates GK with an EC50 60 nM, increases affinity for by approximately 10-fold, exhibits moderate clearance and good oral bioavailability in multiple animal models, lowers excursion following tolerance test ob/ob mouse model diabetes.
The activity of the pyruvate dehydrogenase multienzyme complex (PDC), which catalyses oxidation to acetyl-CoA within mitochondrion, is diminished in animal models diabetes. Studies with purified PDC components have suggested that kinases responsible for inactivating decarboxylase catalytic subunits are most efficient their regulatory role when they bound dihydrolipoyl acetyltransferase (E2) subunits, form structural core complex. We report addition an exogenous E2 subdomain (inner lipoyl...