Athiwat Hutchaleelaha
Millennium Pharmaceuticals
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Publication
Featured researches published by Athiwat Hutchaleelaha.
Nature Medicine | 2013
Genmin Lu; Francis DeGuzman; Stanley J. Hollenbach; Mark Karbarz; Keith Abe; Gail Lee; Peng Luan; Athiwat Hutchaleelaha; Mayuko Inagaki; Pamela B. Conley; David R. Phillips; Uma Sinha
Inhibitors of coagulation factor Xa (fXa) have emerged as a new class of antithrombotics but lack effective antidotes for patients experiencing serious bleeding. We designed and expressed a modified form of fXa as an antidote for fXa inhibitors. This recombinant protein (r-Antidote, PRT064445) is catalytically inactive and lacks the membrane-binding γ-carboxyglutamic acid domain of native fXa but retains the ability of native fXa to bind direct fXa inhibitors as well as low molecular weight heparin–activated antithrombin III (ATIII). r-Antidote dose-dependently reversed the inhibition of fXa by direct fXa inhibitors and corrected the prolongation of ex vivo clotting times by such inhibitors. In rabbits treated with the direct fXa inhibitor rivaroxaban, r-Antidote restored hemostasis in a liver laceration model. The effect of r-Antidote was mediated by reducing plasma anti-fXa activity and the non–protein bound fraction of the fXa inhibitor in plasma. In rats, r-Antidote administration dose-dependently and completely corrected increases in blood loss resulting from ATIII-dependent anticoagulation by enoxaparin or fondaparinux. r-Antidote has the potential to be used as a universal antidote for a broad range of fXa inhibitors.
Bioorganic & Medicinal Chemistry Letters | 2009
Penglie Zhang; Wenrong Huang; Lingyan Wang; Liang Bao; Zhaozhong J. Jia; Shawn M. Bauer; Erick A. Goldman; Gary D. Probst; Yonghong Song; Ting Su; Jingmei Fan; Yanhong Wu; Wenhao Li; John Woolfrey; Uma Sinha; Paul Wong; Susan T. Edwards; Ann E. Arfsten; Lane Clizbe; James Kanter; Anjali Pandey; Gary Park; Athiwat Hutchaleelaha; Joseph L. Lambing; Stanley J. Hollenbach; Robert M. Scarborough; Bing-Yan Zhu
Systematic SAR studies of in vitro factor Xa inhibitory activity around compound 1 were performed by modifying each of the three phenyl rings. A class of highly potent, selective, efficacious and orally bioavailable direct factor Xa inhibitors was discovered. These compounds were screened in hERG binding assays to examine the effects of substitution groups on the hERG channel affinity. From the leading compounds, betrixaban (compound 11, PRT054021) has been selected as the clinical candidate for development.
British Journal of Haematology | 2016
Donna Oksenberg; Kobina Dufu; Mira Patel; Chihyuan Chuang; Zhe Li; Qing Xu; Abel Silva-Garcia; Chengjing Zhou; Athiwat Hutchaleelaha; Larysa N. Patskovska; Yury Patskovsky; Steven C. Almo; Uma Sinha; Brian Metcalf; David R. Archer
A major driver of the pathophysiology of sickle cell disease (SCD) is polymerization of deoxygenated haemoglobin S (HbS), which leads to sickling and destruction of red blood cells (RBCs) and end‐organ damage. Pharmacologically increasing the proportion of oxygenated HbS in RBCs may inhibit polymerization, prevent sickling and provide long term disease modification. We report that GBT440, a small molecule which binds to the N‐terminal α chain of Hb, increases HbS affinity for oxygen, delays in vitro HbS polymerization and prevents sickling of RBCs. Moreover, in a murine model of SCD, GBT440 extends the half‐life of RBCs, reduces reticulocyte counts and prevents ex vivo RBC sickling. Importantly, oral dosing of GBT440 in animals demonstrates suitability for once daily dosing in humans and a highly selective partitioning into RBCs, which is a key therapeutic safety attribute. Thus, GBT440 has the potential for clinical use as a disease‐modifying agent in sickle cell patients.
Bioorganic & Medicinal Chemistry Letters | 2009
Penglie Zhang; Liang Bao; Jingmei Fan; Zhaozhong J. Jia; Uma Sinha; Paul Wong; Gary Park; Athiwat Hutchaleelaha; Robert M. Scarborough; Bing-Yan Zhu
Anthranilamide-based benzamidine compound 4 and its N-substituted analogs were designed and examined as factor Xa inhibitors using substituted benzamidines as unconventional S4 binding element. A group of N,N-dialkylbenzamidines (11, 17 and 24) have been discovered as potent factor Xa inhibitors with strong anticoagulant activity and promising oral PK profiles.
Blood Advances | 2017
Deborah Siegal; Genmin Lu; Janet Leeds; Mark Karbarz; Janice Castillo; Vandana Mathur; Athiwat Hutchaleelaha; Uma Sinha; Michael M. Kitt; Matt McClure; Stanley J. Hollenbach; John T. Curnutte; Pamela B. Conley; Mark Crowther
Direct factor Xa (FXa) inhibitors lack a specific reversal agent for emergencies such as major bleeding or urgent surgery. Andexanet alfa, a modified, catalytically inactive, recombinant human FXa derivative, reverses anticoagulant effect by binding and sequestering FXa inhibitors. This original report of safety and dose-finding, phase 1 and 2 randomized, double-blind, placebo-controlled studies, investigated various doses of andexanet in healthy volunteers. Phase 1 evaluated the safety and pharmacokinetics of andexanet (n = 24) or placebo (n = 8). In phase 2, andexanet (n = 36) or placebo (n = 18) was administered following steady-state apixaban dosing (5 mg twice daily for 6 days); safety, pharmacokinetics, and pharmacodynamics were assessed. Andexanet plasma concentration increased proportionally with dose, with rapid elimination (terminal elimination half-life, 4.35-7.5 hours). Following apixaban treatment, andexanet rapidly (≤2 minutes) and dose dependently reduced unbound apixaban concentration vs placebo (51% to 89% vs 5% reduction; all P < .05), decreased anti-FXa activity (67.8% to 95.0% vs 7.1% reduction; all P < .05), and restored thrombin generation in 67% to 100% vs 6% of subjects (all P < .01), maintaining these effects during continuous 45- and 120-minute infusions. Andexanet was well tolerated. Nine subjects had mild/moderate infusion reactions not associated with hemodynamic changes or respiratory compromise that generally resolved without intervention or dose reduction. There were no thrombotic events or other serious safety issues. In conclusion, andexanet reversed apixaban-mediated effects on pharmacodynamic markers of anticoagulation in healthy volunteers within minutes after administration and for the duration of infusion. This trial was registered at www.clinicaltrials.gov as #NCT01758432.
Physiological Reports | 2016
Xin Geng; Kobina Dufu; Athiwat Hutchaleelaha; Qing Xu; Zhe Li; Chien‐Ming Li; Mira Patel; Nicholas Vlahakis; Josh Lehrer-Graiwer; Donna Oksenberg
Although exertional dyspnea and worsening hypoxia are hallmark clinical features of idiopathic pulmonary fibrosis (IPF), no drug currently available could treat them. GBT1118 is a novel orally bioavailable small molecule that binds to hemoglobin and produces a concentration‐dependent left shift of the oxygen–hemoglobin dissociation curve with subsequent increase in hemoglobin–oxygen affinity and arterial oxygen loading. To assess whether pharmacological modification of hemoglobin–oxygen affinity could ameliorate hypoxemia associated with lung fibrosis, we evaluated GBT1118 in a bleomycin‐induced mouse model of hypoxemia and fibrosis. After pulmonary fibrosis and hypoxemia were induced, GBT1118 was administered for eight consecutive days. Hypoxemia was determined by monitoring arterial oxygen saturation, while the severity of pulmonary fibrosis was assessed by histopathological evaluation and determination of collagen and leukocyte levels in bronchoalveolar lavage fluid. We found that hemoglobin modification by GBT1118 had strong antihypoxemic therapeutic effects with improved arterial oxygen saturation to near normal level. Moreover, GBT1118 treatment significantly attenuated bleomycin‐induced lung fibrosis, collagen accumulation, body weight loss, and leukocyte infiltration. This study is the first to suggest the beneficial effects of hemoglobin modification in fibrotic lungs and offers a promising and novel therapeutic strategy for the treatment of hypoxemia associated with chronic fibrotic lung disorders in human, including IPF.
Journal of Medicinal Chemistry | 2002
Anjali Pandey; Deborah Volkots; Joseph M. Seroogy; Jack W. Rose; Jin-Chen Yu; Joseph L. Lambing; Athiwat Hutchaleelaha; Stanley J. Hollenbach; Keith Abe; Neill A. Giese; Robert M. Scarborough
Blood | 2013
Mathur Vandana; Kitt Michael; Lu Genmin; Pamela B. Conley; Hollenbach Stanley; Janice Castillo; Athiwat Hutchaleelaha; Mark Karbarz; Joyce Lin; Lee Barron; Sandra Russell; Gallia G. Levy; Stuart J. Connolly; John T. Curnutte
Bioorganic & Medicinal Chemistry Letters | 2004
Zhaozhong J. Jia; Yanhong Wu; Wenrong Huang; Penglie Zhang; Yonghong Song; John Woolfrey; Uma Sinha; Ann E. Arfsten; Susan T. Edwards; Athiwat Hutchaleelaha; Stanley J. Hollennbach; Joseph L. Lambing; Robert M. Scarborough; Bing-Yan Zhu
Bioorganic & Medicinal Chemistry Letters | 2004
Penglie Zhang; Liang Bao; Jingmei Zuckett; Erick A. Goldman; Zhaozhong J. Jia; Ann E. Arfsten; Susan T. Edwards; Uma Sinha; Athiwat Hutchaleelaha; Gary Park; Joseph L. Lambing; Stanley J. Hollenbach; Robert M. Scarborough; Bing-Yan Zhu