Daniel Hovdal
AstraZeneca
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Publication
Featured researches published by Daniel Hovdal.
Journal of Medicinal Chemistry | 2015
Malin Lemurell; Johan Ulander; Susanne Winiwarter; Anders Dahlén; Öjvind Davidsson; Hans Emtenäs; Johan Broddefalk; Marianne Swanson; Daniel Hovdal; Alleyn T. Plowright; Anna Pettersen; Marie Rydén-Landergren; Jonas G. Barlind; Antonio Llinas; Margareta Herslöf; Tomas Drmota; Kalle Sigfridsson; Sara Moses; Carl Whatling
A drug discovery program in search of novel 5-lipoxygenase activating protein (FLAP) inhibitors focused on driving a reduction in lipophilicity with maintained or increased ligand lipophilic efficiency (LLE) compared to previously reported compounds led to the discovery of AZD6642 (15b). Introduction of a hydrophilic tetrahydrofuran (THF) ring at the stereogenic central carbon atom led to a significant shift in physicochemical property space. The structure-activity relationship exploration and optimization of DMPK properties leading to this compound are described in addition to pharmacokinetic analysis and an investigation of the pharmacokinetic (PK)-pharmacodynamic (PD) relationship based on ex vivo leukotriene B4 (LTB4) levels in dog. AZD6642 shows high specific potency and low lipophilicity, resulting in a selective and metabolically stable profile. On the basis of initial PK/PD relation measured, a low dose to human was predicted.
Bioorganic & Medicinal Chemistry Letters | 2014
Fabrizio Giordanetto; Peter Bach; Fredrik Zetterberg; Thomas Antonsson; Ruth Bylund; Johan Johansson; Mikael Sellén; David W. Brown; Lotta Hideståhl; Pia Berntsson; Daniel Hovdal; Helen Zachrisson; Jan-Arne Björkman; J.J.J. van Giezen
Modification of a series of P2Y12 receptor antagonists by replacement of the ester functionality was aimed at minimizing the risk of in vivo metabolic instability and pharmacokinetic variability. The resulting ketones were then optimized for their P2Y12 antagonistic and anticoagulation effects in combination with their physicochemical and absorption profiles. The most promising compound showed very potent antiplatelet action in vivo. However, pharmacodynamic-pharmacokinetic analysis did not reveal a significant separation between its anti-platelet and bleeding effects. The relevance of receptor binding kinetics to the in vivo profile is described.
PLOS ONE | 2015
Ola Fjellström; Niklas Larsson; Shin-ichiro Yasuda; Takuma Tsuchida; Takahiro Oguma; Anna Marley; Charlotte Wennberg-Huldt; Daniel Hovdal; Hajime Fukuda; Yukimi Yoneyama; Kazuyo Sasaki; Anders Johansson; Sara Lundqvist; Johan Brengdahl; Richard J. Isaacs; Daniel G. Brown; Stefan Geschwindner; Lambertus Benthem; Claire Priest; Andrew V. Turnbull
Type 2 diabetes (T2D) occurs when there is insufficient insulin release to control blood glucose, due to insulin resistance and impaired β-cell function. The GPR39 receptor is expressed in metabolic tissues including pancreatic β-cells and has been proposed as a T2D target. Specifically, GPR39 agonists might improve β-cell function leading to more adequate and sustained insulin release and glucose control. The present study aimed to test the hypothesis that GPR39 agonism would improve glucose stimulated insulin secretion in vivo. A high throughput screen, followed by a medicinal chemistry program, identified three novel potent Zn2+ modulated GPR39 agonists. These agonists were evaluated in acute rodent glucose tolerance tests. The results showed a lack of glucose lowering and insulinotropic effects not only in lean mice, but also in diet-induced obese (DIO) mice and Zucker fatty rats. It is concluded that Zn2+ modulated GPR39 agonists do not acutely stimulate insulin release in rodents.
European Journal of Pharmaceutical Sciences | 2018
Joachim Almquist; Daniel Hovdal; Christine Ahlström; Ola Fjellström; Peter Gennemark; Monika Sundqvist
Abstract Mathematical models predicting in vivo pharmacodynamic effects from in vitro data can accelerate drug discovery, and reduce costs and animal use. However, data integration and modeling is non‐trivial when more than one drug‐target receptor is involved in the biological response. We modeled the inhibition of non‐esterified fatty acid release by dual G‐protein‐coupled receptor 81/109A (GPR81/GPR109A) agonists in vivo in the rat, to estimate the in vivo EC50 values for 12 different compounds. We subsequently predicted those potency estimates using EC50 values obtained from concentration‐response data in isolated primary adipocytes and cell systems overexpressing GPR81 or GPR109A in vitro. A simple linear regression model based on data from primary adipocytes predicted the in vivo EC50 better than simple linear regression models based on in vitro data from either of the cell systems. Three models combining the data from the overexpressing cell systems were also evaluated: two piecewise linear models defining logical OR‐ and AND‐circuits, and a multivariate linear regression model. All three models performed better than the simple linear regression model based on data from primary adipocytes. The OR‐model was favored since it is likely that activation of either GPR81 or GPR109A is sufficient to deactivate the cAMP pathway, and thereby inhibit non‐esterified fatty acid release. The OR‐model was also able to predict the in vivo selectivity between the two receptors. Finally, the OR‐model was used to predict the in vivo potency of 1651 new compounds. This work suggests that data from the overexpressing cell systems are sufficient to predict in vivo potency of GPR81/GPR109A agonists, an approach contributing to faster and leaner drug discovery. Graphical abstract Figure. No caption available.
Journal of Pharmacokinetics and Pharmacodynamics | 2013
Peter Gennemark; Rasmus Jansson-Löfmark; Gina Hyberg; Maria Wigstrand; Dorota Kakol-Palm; Pernilla Håkansson; Daniel Hovdal; Peter Brodin; Maria Fritsch-Fredin; Madeleine Antonsson; Karolina Ploj; Johan Gabrielsson
Archive | 2009
Thomas Antonsson; Peter Bach; Ruth Bylund; Fabrizio Giordanetto; Daniel Hovdal; Johan Johansson; Mikael Sellen
Archive | 2008
Kosrat Amin; Thomas Antonsson; Christoffer Bengtsson; David Brown; Ruth Bylund; Daniel Hovdal; Fabrizio Giordanetto; Johan Johansson
Circulation | 2016
Johannes Wikström; Daniel Karlsson; Margareta Behrendt; Sara Swedlund; Helena U. Westergren; Daniel Hovdal; Monika Sundquist; Anne-Christine Andréasson; Ann-Cathrine Jönsson-Rylander; Marianne Månsson; Carl Whatling; Li-Ming Gan
Toxicology Letters | 2012
Patrik U. Andersson; Kerstin Kenne; Björn Glinghammar; Amy Pointon; Peter Åkerblad; Mareike Lutz; Daniel Hovdal; Ingela Maxvall; Eva-Lotte Lindstedt
Archive | 2009
Ruth Bylund; Daniel Hovdal; Johan Johansson; Mikael Sellén; Fredrik Zetterberg