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Urban J.,KinDex Therapeutics | Dahlberg C.J.,KinDex Therapeutics | Carroll B.J.,KinDex Therapeutics | Kaminsky W.,University of Washington
Angewandte Chemie - International Edition | Year: 2013

During the beer brewing process, bitter tasting cis and trans iso-α-acids are generated from the precursor α-acids found in hops. The absolute configurations of the α-acid (-)-humulone and several of its derivatives have now been elucidated by X-ray crystallography, thus resolving decades of confusion over the humulone isomerization mechanism. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Konda V.R.,KinDex Therapeutics | Desai A.,KinDex Therapeutics | Darland G.,KinDex Therapeutics | Grayson N.,KinDex Therapeutics | Bland J.S.,KinDex Therapeutics
PLoS ONE | Year: 2014

Aims/Hypothesis: We developed KDT501, a novel substituted 1,3-cyclopentadione chemically derived from hop extracts, and evaluated it in various in vitro and in vivo models of diabetes and insulin sensitivity. Methods: KDT501 was evaluated for anti-inflammatory effects in monocyte/macrophage cells; agonistic activity for peroxisome proliferator-activated receptors (PPAR); lipogenesis and gene expression profile in human subcutaneous adipocytes. Body composition, glucose, insulin sensitivity, and lipids were assessed in diet-induced obesity (DIO) mice and Zucker Diabetic Fatty (ZDF) rats after oral administration. Results: KDT501 mediated lipogenesis in 3T3L1 and human subcutaneous adipocytes; however, the gene expression profile of KDT501 differed from that of the full PPARc agonist rosiglitazone, suggesting that KDT501 has pleiotropic biological activities. In addition, KDT501 showed only modest, partial PPARc agonist activity and exhibited anti-inflammatory effects in monocytes/macrophages that were not observed with rosiglitazone. In a DIO mouse model, oral administration of KDT501 significantly reduced fed blood glucose, glucose/insulin AUC following an oral glucose bolus, and body fat. In ZDF rats, oral administration of KDT501 significantly reduced fed glucose, fasting plasma glucose, and glucose AUC after an oral glucose bolus. Significant, dose-dependent reductions of plasma hemoglobin A1c, weight gain, total cholesterol, and triglycerides were also observed in animals receiving KDT501. Conclusion: These results indicate that KDT501 produces a unique anti-diabetic profile that is distinct in its spectrum of pharmacological effects and biological mechanism from both metformin and pioglitazone. KDT501 may thus constitute a novel therapeutic agent for the treatment of Type 2 diabetes and associated conditions. © 2014 Konda et al.


The present application provides cis 3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-1-one derivatives and substantially enantiomerically pure compositions thereof. These derivatives include (+)-(4S,5R)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-1-one, ()-(4R,5S)-3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-1-one, and salts and crystals thereof. The application further provides methods of using the disclosed compounds and compositions to activate PPAR, activate GPR120, inhibit inflammation, and treat conditions responsive to PPAR modulation, conditions responsive to GPR120 modulation, and metabolic disturbances such as diabetes.


Trademark
KinDex Therapeutics | Date: 2012-05-11

Diabetes treating agents; pharmaceutical preparations for treating diabetes; pharmaceutical preparations and substances for the treatment of metabolic and inflammatory diseases and disorders.


KinDex Therapeutics | Entity website

Scientific Advisors Ginger Constantine, MD Ginger initiated EndoRheum Consultants, an organization dedicated to assisting companies with all clinical aspects of drug development, in 2010. Prior to EndoRheum, she was associated with Wyeth Pharmaceuticals as both a Rheumatology Consultant and later as part of their Medical Affairs group ...


KinDex Therapeutics | Entity website

KinDexs unique positioning is based on modulation of TAS2Rs, a group of GPCR receptors that influence endocrine and immune systems in multiple tissue types, including the small intestine, liver, lungs and gonads. Our most advanced candidate, KDT501 is an orally dosed small molecule that normalizes body weight and glucose and improves cyclicity, ovulation and testosterone levels in rodent models of metabolic disease and PCOS ...


PubMed | KinDex Therapeutics
Type: Journal Article | Journal: Global advances in health and medicine : improving healthcare outcomes worldwide | Year: 2013

Niacin favorably modifies cardiovascular risk factors but is associated with flushing and shows limited benefit in improving endothelial function. We investigated whether combining anti-inflammatory tetrahydro-iso-alpha acids (THIAA) from hops with niacin would improve endothelial function. We hypothesized that the THIAA+niacin combination would demonstrate benefits not seen with niacin alone. In an in vitro model, a THIAA+niacin mixture inhibited several TNF--induced cytokines in human aortic endothelial cells and in human monocytic cells and was significantly more efficacious than niacin alone. Subsequently, the effect of 125 mg THIAA and 500 mg niacin on endothelial-regulated flow-mediated vasodilation (FMD) was explored in a pilot study of 11 dyslipidemic volunteers. The 12-week treatment (2 tablets/day) resulted in a clinically relevant FMD increase compared to a trend toward an FMD decrease with placebo; the between-arm difference was statistically significant. THIAA+niacin treatment also improved total cholesterol, low-density lipoprotein cholesterol, and uric acid. No significant improvement in these parameters was observed with placebo. High-sensitivity C-reactive protein was significantly increased only in the placebo arm. Nutritional support with a THIAA+niacin combination may provide benefits for endothelial function in those with dyslipidemia.


PubMed | KinDex Therapeutics
Type: Journal Article | Journal: Global advances in health and medicine : improving healthcare outcomes worldwide | Year: 2013

Patients do not just wake up one morning with cardiac disease. Instead there is an extended preclinical phase during which lifestyle choices determine outcome. Recent advances in our understanding of oxidative stress, endocrine signaling, immune/inflammatory balance, and energy production illuminate opportunities for efficacious intervention. A thorough exploration of these pathophysiologies will allow physicians the opportunity to offer their patients a journey away from illness and disease to optimal wellness.


PubMed | KinDex Therapeutics
Type: Journal Article | Journal: PloS one | Year: 2014

We developed KDT501, a novel substituted 1,3-cyclopentadione chemically derived from hop extracts, and evaluated it in various in vitro and in vivo models of diabetes and insulin sensitivity.KDT501 was evaluated for anti-inflammatory effects in monocyte/macrophage cells; agonistic activity for peroxisome proliferator-activated receptors (PPAR); lipogenesis and gene expression profile in human subcutaneous adipocytes. Body composition, glucose, insulin sensitivity, and lipids were assessed in diet-induced obesity (DIO) mice and Zucker Diabetic Fatty (ZDF) rats after oral administration.KDT501 mediated lipogenesis in 3T3L1 and human subcutaneous adipocytes; however, the gene expression profile of KDT501 differed from that of the full PPAR agonist rosiglitazone, suggesting that KDT501 has pleiotropic biological activities. In addition, KDT501 showed only modest, partial PPAR agonist activity and exhibited anti-inflammatory effects in monocytes/macrophages that were not observed with rosiglitazone. In a DIO mouse model, oral administration of KDT501 significantly reduced fed blood glucose, glucose/insulin AUC following an oral glucose bolus, and body fat. In ZDF rats, oral administration of KDT501 significantly reduced fed glucose, fasting plasma glucose, and glucose AUC after an oral glucose bolus. Significant, dose-dependent reductions of plasma hemoglobin A1c, weight gain, total cholesterol, and triglycerides were also observed in animals receiving KDT501.These results indicate that KDT501 produces a unique anti-diabetic profile that is distinct in its spectrum of pharmacological effects and biological mechanism from both metformin and pioglitazone. KDT501 may thus constitute a novel therapeutic agent for the treatment of Type 2 diabetes and associated conditions.

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