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Daniel A Tatosian, Nadia Cardillo Marricco, Xiaoli Shirley Glasgow, Bruce DeGroot, Katherine Dunnington, Laura George, Isaias Noel Gendrano, Amy O Johnson-Levonas, Dennis Swearingen, Eunkyung Kauh
Omarigliptin is a dipeptidyl peptidase-4 inhibitor being developed as a once-weekly treatment for type 2 diabetes. This double-blind, double-dummy, randomized, 3-period balanced crossover study definitively evaluated the effects of a supratherapeutic omarigliptin dose on QTc interval. Population-specific correction of QT interval (QTcP) was used for the primary analysis. Healthy subjects (n = 60) were enrolled and received treatments separated by a ≥4-week washout: (1) single-dose 25 mg omarigliptin (day 1), single-dose 175 mg omarigliptin (day 2); (2) placebo (day 1) followed by single-dose 400 mg moxifloxacin (day 2); (3) placebo (days 1 and 2)...
September 2016: Clinical Pharmacology in Drug Development
Carol Addy, Daniel A Tatosian, Xiaoli S Glasgow, Isaias Noel Gendrano Iii, Christine McCrary Sisk, Eunkyung A Kauh, S Aubrey Stoch, John A Wagner
Omarigliptin is being developed as a potent, once-weekly, oral dipeptidyl peptidase-4 inhibitor for the treatment of type 2 diabetes. This double-blind, randomized, placebo-controlled study evaluated the effects of age, sex, and obesity on the pharmacokinetics of omarigliptin in healthy subjects. A single oral dose of omarigliptin 10 mg (n = 6/panel) or placebo (n = 2/panel) was administered in the fasted state to elderly nonobese men and women, young obese (30 ≤ body mass index [BMI] ≤ 35 kg/m(2) ) men and women, and young nonobese women of nonchildbearing potential...
September 2016: Clinical Pharmacology in Drug Development
Philip M S Evans, Stephen C Bain
INTRODUCTION: The estimated global prevalence of diabetes mellitus for adults aged 20-70 in 2015 was 415 million with approximately 90% of diagnosed cases being Type 2 diabetes mellitus (T2DM). Improvements in lifestyle and effective therapies are key to management but due to the progressive nature of T2DM, pharmacotherapy is typically required. Whilst the initial therapy will usually be with metformin, thereafter treatment should be individualised, with consideration of several different second line options...
October 2016: Expert Opinion on Pharmacotherapy
Shiliang Li, Hongling Xu, Shichao Cui, Fangshu Wu, Youli Zhang, Mingbo Su, Yinghui Gong, Shaobing Qiu, Qian Jiao, Chun Qin, Jiwei Shan, Ming Zhang, Jiawei Wang, Qiao Yin, Minghao Xu, Xiaofeng Liu, Rui Wang, Lili Zhu, Jia Li, Yufang Xu, Hualiang Jiang, Zhenjiang Zhao, Jingya Li, Honglin Li
Starting from the lead isodaphnetin, a natural product inhibitor of DPP-4 discovered through a target fishing docking based approach, a series of novel 2-phenyl-3,4-dihydro-2H-benzo[f]chromen-3-amine derivatives as potent DPP-4 inhibitors are rationally designed utilizing highly efficient 3D molecular similarity based scaffold hopping as well as electrostatic complementary methods. Those ingenious drug design strategies bring us approximate 7400-fold boost in potency. Compounds 22a and 24a are the most potent ones (IC50 ≈ 2...
July 28, 2016: Journal of Medicinal Chemistry
Xueying Tan
Omarigliptin is a new once-weekly dipeptidyl peptidase-4 (DPP-4) inhibitor developed for the treatment of type 2 diabetes. It is indicated to have favorable effects on glycosylated hemoglobin (HbA1c), fasting and postmeal plasma glucose. It potently but reversibly inhibits DPP-4 enzyme, which prolongs the circulating half-life of glucagon-like peptide-1 that increases insulin secretion in a glucose-dependent manner. Benefiting from glucose-dependent insulin secretion, omarigliptin is associated with low risk of hypoglycemia...
July 2, 2016: Endocrine
Sumei Ren, Donald Gauthier, Rosemary Marques, Roy Helmy, David Hesk
An efficient synthesis for [(14) C]Omarigliptin (MK-3102) is described. The initial synthesis of a key (14) C-pyrazole moiety did not work due to the lack of stability of (14) C-DMF-DMA reagent. Thus, a new radiolabeled synthon, (14) C-biphenylmethylformate, was synthesized from (14) C-sodium formate in one step in 92% yield and successfully used in construction of the key (14) C-pyrazole moiety. Regioselective N-sulfonation of the pyrazole moiety was achieved through a dehydration-sulfonation-isomerization sequence...
August 2016: Journal of Labelled Compounds & Radiopharmaceuticals
Rajesh Krishna, Carol Addy, Daniel Tatosian, Xiaoli S Glasgow, Isaias Noel Gendrano Iii, Martine Robberechts, Wouter Haazen, J N de Hoon, Marleen Depré, Ashley Martucci, Joanna Z Peng, Amy O Johnson-Levonas, John A Wagner, S Aubrey Stoch
The pharmacokinetics (PK), and pharmacodynamics (PD) of omarigliptin, a novel once-weekly DPP-4 inhibitor, were assessed following single and multiple doses in healthy subjects. Absorption was rapid and food did not influence single dose PK. Accumulation was minimal and steady state was reached after 2-3 weeks. Weekly AUC and Cmax displayed dose proportionality within the dose range studied at steady state. The average renal clearance of omarigliptin was ∼2 L/h. DPP-4 inhibition ranged from ∼77-89% at 168 hours following the last of 3 once-weekly doses over the dose range studied...
May 26, 2016: Journal of Clinical Pharmacology
Sanjay Kalra, Yashdeep Gupta
This article introduces the concept of "weekend therapy", which has now become reality in diabetes. It briefly describes injectable and oral drugs which are currently available, or are in advanced stages of development, for use in once weekly administration. These include dulaglutide, exenatide QW, semaglutide, omarigliptin and trelagliptin.
May 2016: JPMA. the Journal of the Pakistan Medical Association
Saori Tsuchiya, Evan Friedman, Carol Addy, Akira Wakana, Daniel Tatosian, Yuki Matsumoto, Hideyo Suzuki, Eunkyung Kauh
INTRODUCTION: Omarigliptin is a novel, potent, long-acting oral dipeptidyl peptidase-4 (DPP-4) inhibitor being developed as a once-weekly (q.w.) treatment for type 2 diabetes mellitus (T2DM) patients, with 25 mg and 12.5 mg tablets recently being approved as market formulations in Japan. MATERIALS AND METHODS: This was a two-part, double-blind, randomized, placebo-controlled study in healthy Japanese male subjects to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of omarigliptin after single dose (5-100 mg) and multiple dose (1-50 mg q...
May 10, 2016: Journal of Diabetes Investigation
Carol Addy, Daniel Tatosian, Xiaoli S Glasgow, Isaias N Gendrano, Eunkyung Kauh, Ashley Martucci, Amy O Johnson-Levonas, Diana Selverian, Catherine Z Matthews, Marie Gutierrez, John A Wagner, S Aubrey Stoch
PURPOSE: Omarigliptin (MK-3102) is a potent, oral, long-acting dipeptidyl peptidase (DPP)-4 inhibitor approved in Japan and in global development as a once-weekly treatment for type 2 diabetes mellitus (T2DM). The aim of this study was to investigate the pharmacokinetic (PK) and pharmacodynamic (PD) effects of omarigliptin in obese participants with and without T2DM. METHODS: This was a Phase I, randomized, double-blind, placebo-controlled, multiple-dose study of 50-mg omarigliptin administered once weekly for 4 weeks...
March 2016: Clinical Therapeutics
Ping Chen, Dennis Feng, Xiaoxia Qian, James Apgar, Robert Wilkening, Jeffrey T Kuethe, Ying-Duo Gao, Giovanna Scapin, Jason Cox, George Doss, George Eiermann, Huaibing He, Xiaohua Li, Kathryn A Lyons, Joseph Metzger, Aleksandr Petrov, Joseph K Wu, Shiyao Xu, Ann E Weber, Youwei Yan, Ranabir Sinha Roy, Tesfaye Biftu
A series of novel substituted-[(3R)-amino-2-(2,5-difluorophenyl)]tetrahydro-2H-pyran analogs have been prepared and evaluated as potent, selective and orally active DPP-4 inhibitors. These efforts lead to the discovery of a long acting DPP-4 inhibitor, omarigliptin (MK-3102), which recently completed phase III clinical development and has been approved in Japan.
December 15, 2015: Bioorganic & Medicinal Chemistry Letters
Celeste B Burness
Omarigliptin [Marizev(®) (Japan)] is a small-molecule dipeptidyl peptidase-4 (DPP-4) inhibitor developed by Merck for the oral treatment of type 2 diabetes (T2DM). Unlike the majority of other approved agents of its class, which are usually administered once daily, omarigliptin can be administered once weekly. Once-weekly omarigliptin has received its first global approval in this indication in Japan, for use in adults. Phase III clinical development of the product is underway in several other countries. This article summarizes the milestones in the development of omarigliptin leading to this first approval for the treatment of T2DM...
November 2015: Drugs
Wayne H-H Sheu, Ira Gantz, Menghui Chen, Shailaja Suryawanshi, Arpana Mirza, Barry J Goldstein, Keith D Kaufman, Samuel S Engel
OBJECTIVE: This study was conducted to determine the optimal dose of omarigliptin, a once-weekly (q.w.) dipeptidyl peptidase IV (DPP-4) inhibitor, for the treatment of patients with type 2 diabetes and evaluate the long-term safety of that dose. RESEARCH DESIGN AND METHODS: In a multicenter, double-blind, 12-week, dose-range finding study, 685 oral antihyperglycemic agent-naïve or washed-out subjects with type 2 diabetes were randomized to one of five once-weekly doses of omarigliptin (0...
November 2015: Diabetes Care
Tesfaye Biftu, Ranabir Sinha-Roy, Ping Chen, Xiaoxia Qian, Dennis Feng, Jeffrey T Kuethe, Giovanna Scapin, Ying Duo Gao, Youwei Yan, Davida Krueger, Annette Bak, George Eiermann, Jiafang He, Jason Cox, Jacqueline Hicks, Kathy Lyons, Huaibing He, Gino Salituro, Sharon Tong, Sangita Patel, George Doss, Aleksandr Petrov, Joseph Wu, Shiyao Sherrie Xu, Charles Sewall, Xiaoping Zhang, Bei Zhang, Nancy A Thornberry, Ann E Weber
In our effort to discover DPP-4 inhibitors with added benefits over currently commercially available DPP-4 inhibitors, MK-3102 (omarigliptin), was identified as a potent and selective dipeptidyl peptidase 4 (DPP-4) inhibitor with an excellent pharmacokinetic profile amenable for once-weekly human dosing and selected as a clinical development candidate. This manuscript summarizes the mechanism of action, scientific rationale, medicinal chemistry, pharmacokinetic properties, and human efficacy data for omarigliptin, which is currently in phase 3 clinical development...
April 24, 2014: Journal of Medicinal Chemistry
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