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Buil M.A.,Almirall R and nter | Calbet M.,Almirall R and nter | Castillo M.,Almirall Barcelona Science Park Unit | Castro J.,Almirall R and nter | And 11 more authors.
European Journal of Medicinal Chemistry | Year: 2016

Monocyclic and bicyclic ring systems were investigated as the "core" section of a series of diphenylsulphone-containing acetic acid CRTh2 receptor antagonists. A range of potencies were observed and single-digit nanomolar potencies were obtained in both the monocyclic and bicyclic cores. Residence times for the monocyclic compounds were very short. Some of the bicyclic cores displayed better residence times. A methyl group in the northern part of the core, between the head and tail was a necessary requirement for the beginnings of long residence times. Variations of the tail substitution maximised potencies and residence times. © 2016 Elsevier Masson SAS. All rights reserved.

Forns P.,Almirall Barcelona Science Park Unit | Esteve C.,Almirall Research Center | Taboada L.,Almirall Research Center | Alonso J.A.,Almirall Research Center | And 7 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2012

A series of aminopyrazines as inhibitors of Syk kinase activity and showing inhibition of LAD2 cells degranulation is described. Optimization of the carboxamide motif with aminomethylpiperidines provided high potency inhibiting Syk but low cellular activity. Amides of cis and trans adamantanol showed good inhibitory activity against Syk as well as remarkable activity in LAD2 cells degranulation assay. © 2012 Elsevier Ltd. All rights reserved.

Alonso J.A.,Almirall R and nter | Andres M.,Almirall R and nter | Bravo M.,Almirall R and nter | Buil M.A.,Almirall R and nter | And 17 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2014

The correct positioning and orientation of an hydrogen bond acceptor (HBA) in the tail portion of the biaryl series of CRTh2 antagonists is a requirement for long receptor residence time. The HBA in combination with a small steric substituent in the core section (Rcore ≈ H) gives access to compounds with dissociation half-lives of ≥24 h. © 2014 Elsevier Ltd. All rights reserved.

Ramis I.,Almirall R and nter | Otal R.,Almirall R and nter | Carreno C.,Almirall R and nter | Domenech A.,Almirall R and nter | And 8 more authors.
Pharmacological Research | Year: 2015

Spleen tyrosine kinase (Syk) is essential for signal transduction of immunoreceptors. Inhibition of Syk abrogates mast cell degranulation and B cell responses. We hypothesized that Syk inhibition in the lung by inhaled route could block airway mast cells degranulation and the early asthmatic response without the need of systemic exposure. We discovered LAS189386, a novel Syk inhibitor with suitable properties for inhaled administration. The aim of this study was to characterize the in vitro and in vivo profile of LAS189386. The compound was profiled in Syk enzymatic assay, against a panel of selected kinases and in Syk-dependent cellular assays in mast cells and B cells. Pharmacokinetics and in vivo efficacy was assessed by intratracheal route. Airway resistance and mast cell degranulation after OVA challenge was evaluated in an ovalbumin-sensitized Brown Norway rat model. LAS189386 potently inhibits Syk enzymatic activity (IC50 7.2 nM), Syk phosphorylation (IC50 41 nM), LAD2 cells degranulation (IC50 56 nM), and B cell activation (IC50 22 nM). LAS189386 inhibits early asthmatic response and airway mast cell degranulation without affecting systemic mast cells. The present results support the hypothesis that topical inhibition of Syk in the lung, without systemic exposure, is sufficient to inhibit EAR in rats. Syk inhibition by inhaled route constitutes a promising therapeutic option for asthma. © 2015 Elsevier Ltd. All rights reserved.

Andres M.,Almirall Randnter | Bravo M.,Almirall Randnter | Buil M.A.,Almirall Randnter | Calbet M.,Almirall Randnter | And 8 more authors.
European Journal of Medicinal Chemistry | Year: 2014

In this manuscript, the synthesis and biological activity of a series of pyrazole acetic acid derivatives as CRTh2 antagonists is presented. Biological evaluation in vitro revealed that the pyrazole core showed in several cases a different structure-activity relationship (SAR) to that of related indole acetic acid. A potent series of ortho-sulfonyl benzyl substituents was found, from which compounds 27 and 63 were advanced to in vivo profiling. © 2013 Elsevier Masson SAS. All rights reserved.

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