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Featured researches published by Jo Alen.


Bioorganic & Medicinal Chemistry Letters | 2013

3-[2-(Aminomethyl)-5-[(pyridin-4-yl)carbamoyl]phenyl] benzoates as soft ROCK inhibitors.

Sandro Boland; Olivier Defert; Jo Alen; Arnaud Bourin; Karolien Castermans; Nele Kindt; Nicki Boumans; Laura Panitti; Sarah Van de Velde; Ingeborg Stalmans; Dirk Leysen

Clinical development of ROCK inhibitors has so far been limited by systemic or local ROCK-associated side effects. A soft drug approach, which involves predictable metabolic inactivation of an active compound to a nontoxic metabolite, could represent an attractive way to obtain ROCK inhibitors with improved tolerability. We herein report the design and synthesis of a new series of soft ROCK inhibitors structurally related to the ROCK inhibitor Y-27632. These inhibitors contain carboxylic ester moieties which allow inactivation by esterases. While the parent esters display strong activity in enzymatic (ROCK2) and cellular (MLC phosphorylation) assays, their corresponding carboxylic acid metabolites have negligible functional activity. Compound 32 combined strong efficacy (ROCK2 IC50=2.5 nM) with rapid inactivation in plasma (t1/2 <5). Compound 32 also demonstrated in vivo efficacy when evaluated as an IOP-lowering agent in ocular normotensive New-Zealand White rabbits, without ocular side effects.


Journal of Medicinal Chemistry | 2015

Design, Synthesis, and Biological Evaluation of Novel, Highly Active Soft ROCK Inhibitors

Sandro Boland; Arnaud Pierre Jean Bourin; Jo Alen; Jacques Geraets; Pieter Schroeders; Karolien Castermans; Nele Kindt; Nicki Boumans; Laura Panitti; Silke Fransen; Jessica Vanormelingen; Jean Marie Stassen; Dirk Leysen; Olivier Defert

ROCK1 and ROCK2 play important roles in numerous cellular functions, including smooth muscle cell contraction, cell proliferation, adhesion, and migration. Consequently, ROCK inhibitors are of interest for treating multiple indications including cardiovascular diseases, inflammatory and autoimmune diseases, lung diseases, and eye diseases. However, systemic inhibition of ROCK is expected to result in significant side effects. Strategies allowing reduced systemic exposure are therefore of interest. In a continuing effort toward identification of ROCK inhibitors, we here report the design, synthesis, and evaluation of novel soft ROCK inhibitors displaying an ester function allowing their rapid inactivation in the systemic circulation. Those compounds display subnanomolar activity against ROCK and strong differences of functional activity between parent compounds and expected metabolites. The binding mode of a representative compound was determined experimentally in a single-crystal X-ray diffraction study. Enzymes responsible for inactivation of these compounds once they enter systemic circulation are also discussed.


Bioorganic & Medicinal Chemistry Letters | 2015

Design, synthesis and biological characterization of selective LIMK inhibitors.

Sandro Boland; Arnaud Bourin; Jo Alen; Jacques Geraets; Pieter Schroeders; Karolien Castermans; Nele Kindt; Nicki Boumans; Laura Panitti; Jessica Vanormelingen; Silke Fransen; Sarah Van de Velde; Olivier Defert

Inhibitors of LIM kinases are considered of interest for several indications, including elevated intraocular pressure (IOP), cancer, or infection by HIV-1. LX-7101 (Lexicon Pharmaceuticals) was advanced to Phase-I clinical trials as an IOP-lowering agent for treatment of glaucoma. We here discuss the design, synthesis and evaluation of LIMK inhibitors based on a pyrrolopyrimidine scaffold, which represent close analogs of LX-7101. Exploration of structure-activity relationships revealed that many of such compounds, including LX-7101, cause potent inhibition of LIMK1 and LIMK2, and also ROCK2 and PKA. Molecular variations around the various structural elements of LX-7101 were attempted. Substitution on position 6 of the pyrrolopyrimidine scaffold led to the identification of LX-7101 analogs displaying good selectivity versus ROCK, PKA and Akt.


Bioorganic & Medicinal Chemistry Letters | 2014

Novel Roflumilast analogs as soft PDE4 inhibitors

Sandro Boland; Jo Alen; Arnaud Bourin; Karolien Castermans; Nicki Boumans; Laura Panitti; Jessica Vanormelingen; Dirk Leysen; Olivier Defert

PDE4 inhibitors are of high interest for treatment of a wide range of inflammatory or autoimmune diseases. Their potential however has not yet been realized due to target-associated side effects, resulting in a low therapeutic window. We herein report the design, synthesis and evaluation of novel PDE4 inhibitors containing a γ-lactone structure. Such molecules are designed to undergo metabolic inactivation when entering circulation, thereby limiting systemic exposure and reducing the risk for side effects. The resulting inhibitors were highly active on both PDE4B1 and PDE4D2 and underwent rapid degradation in human plasma by paraoxonase 1. In contrast, their metabolites displayed markedly reduced permeability and/or on-target activity.


Archive | 2012

NOVEL ROCK KINASE INHIBITORS

Jo Alen; Sandro Boland; Arnaud Pierre Jean Bourin; Olivier Defert; Dirk Leysen


Archive | 2012

NOVEL ROCK INHIBITORS

Dirk Leysen; Olivier Defert; Sandro Boland; Jo Alen; Arnaud Pierre Jean Bourin


Archive | 2012

NOVEL SOFT ROCK INHIBITORS

Jo Alen; Sandro Boland; Arnaud Pierre Jean Bourin; Olivier Defert; Dirk Leysen


Archive | 2012

BIPHENYLCARBOXAMIDES AS ROCK KINASE INHIBITORS

Jo Alen; Sandro Boland; Arnaud Pierre Jean Bourin; Olivier Defert; Dirk Leysen


Archive | 2017

bifenilcarboxamidas como inibidores de quinase rock

Arnaud Pierre Jean Bourin; Dirk Leysen; Jo Alen; Olivier Defert; Sandro Boland


Archive | 2017

inibidores leves de rock

Arnaud Pierre Jean Bourin; Dirk Leysen; Jo Alen; Olivier Defert; Sandro Boland

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Sandro Boland

Katholieke Universiteit Leuven

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Sarah Van de Velde

Katholieke Universiteit Leuven

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Ingeborg Stalmans

Katholieke Universiteit Leuven

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