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Featured researches published by Magnus Polla.


Bioorganic & Medicinal Chemistry | 2014

Design and synthesis of conformationally restricted inhibitors of active thrombin activatable fibrinolysis inhibitor (TAFIa).

Mikael Dan Brink; Anders Dahlén; Thomas Olsson; Magnus Polla; Tor Svensson

A series of 4,5,6,7-tetrahydro-1H-benzimidazole-5-carboxylic acid and 5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-7-carboxylic acid derivatives designed as inhibitors of TAFIa has been prepared via a common hydrogenation-alkylation sequence starting from the appropriate benzimidazole and imidazopyridine system. We present a successful design strategy using a conformational restriction approach resulting in potent and selective inhibitors of TAFIa. The X-ray structure of compound 5 in complex with a H333Y/H335Q double mutant TAFI indicate that the conformational restriction is responsible for the observed potency increase.


Journal of Medicinal Chemistry | 2016

Macrocyclic Prodrugs of a Selective Nonpeptidic Direct Thrombin Inhibitor Display High Permeability, Efficient Bioconversion but Low Bioavailability

Vincent Andersson; Fredrik Bergström; Jonas Brånalt; Gunnar Grönberg; David Gustafsson; Staffan Karlsson; Magnus Polla; Joakim Bergman; Jan Kihlberg

The only oral direct thrombin inhibitors that have reached the market, ximelagatran and dabigatran etexilat, are double prodrugs with low bioavailability in humans. We have evaluated an alternative strategy: the preparation of a nonpeptidic, polar direct thrombin inhibitor as a single, macrocyclic esterase-cleavable (acyloxy)alkoxy prodrug. Two homologous prodrugs were synthesized and displayed high solubilities and Caco-2 cell permeabilities, suggesting high absorption from the intestine. In addition, they were rapidly and completely converted to the active zwitterionic thrombin inhibitor in human hepatocytes. Unexpectedly, the most promising prodrug displayed only moderately higher oral bioavailability in rat than the polar direct thrombin inhibitor, most likely due to rapid metabolism in the intestine or the intestinal wall. To the best of our knowledge, this is the first in vivo ADME study of macrocyclic (acyloxy)alkoxy prodrugs, and it remains to be established if the modest increase in bioavailability is a general feature of this category of prodrugs or not.


Journal of Computer-aided Molecular Design | 2012

Composite multi-parameter ranking of real and virtual compounds for design of MC4R agonists: renaissance of the Free-Wilson methodology.

Ingemar Nilsson; Magnus Polla

Drug design is a multi-parameter task present in the analysis of experimental data for synthesized compounds and in the prediction of new compounds with desired properties. This article describes the implementation of a binned scoring and composite ranking scheme for 11 experimental parameters that were identified as key drivers in the MC4R project. The composite ranking scheme was implemented in an AstraZeneca tool for analysis of project data, thereby providing an immediate re-ranking as new experimental data was added. The automated ranking also highlighted compounds overlooked by the project team. The successful implementation of a composite ranking on experimental data led to the development of an equivalent virtual score, which was based on Free-Wilson models of the parameters from the experimental ranking. The individual Free-Wilson models showed good to high predictive power with a correlation coefficient between 0.45 and 0.97 based on the external test set. The virtual ranking adds value to the selection of compounds for synthesis but error propagation must be controlled. The experimental ranking approach adds significant value, is parameter independent and can be tuned and applied to any drug discovery project.


Bioorganic & Medicinal Chemistry | 2004

Design and synthesis of potent, orally active, inhibitors of carboxypeptidase U (TAFIa)

Magnus Polla; Louise Tottie; Carita Nordén; Marcel Linschoten; Djordje Musil; Susanne Trumpp-Kallmeyer; Inger Reidun F. Aukrust; Rune Ringom; Kjetil Holm; Siren M. Neset; Marcel Sandberg; John Thurmond; Peng Yu; Georgeta Hategan; Herb Anderson


Archive | 1998

Novel bispidine antiarrhythmic compounds

Gert Strandlund; Christer Alstermark; Annika Björe; Magnus Björsne; Marianne Frantsi; Torbjörn Halvarsson; Kurt-Jürgen Hoffmann; Eva-Lotte Lindstedt; Magnus Polla


Analytical Biochemistry | 2006

The intrinsic enzymatic activity of plasma procarboxypeptidase U (TAFI) can interfere with plasma carboxypeptidase N assays.

Johan Willemse; Magnus Polla; Dirk Hendriks


Clinica Chimica Acta | 2008

Comparative substrate specificity study of carboxypeptidase U (TAFIa) and carboxypeptidase N: Development of highly selective CPU substrates as useful tools for assay development

Johan Willemse; Magnus Polla; Thomas Olsson; Dirk Hendriks


Archive | 2000

A pharmaceutical formulation containing an inhibitor of carboxypeptidase u and a thrombin inhibitor

Tommy Abrahamsson; Viveca Nerme; Magnus Polla


Archive | 1998

Bispidine antiarrhythmic compounds

Christer Alstermark; Annika Björe; Magnus Björsne; Marianne Frantsi; Torbjörn Halvarsson; Kurt-Jürgen Hoffmann; Eva-Lotte Lindstedt; Magnus Polla; Gert Strandlund


Archive | 2003

2,5-disubstituted 3-mercaptopentanoic acid

Magnus Polla

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