Peter Eichhorn

Structure-activity relationships (SAR) and structure-kinetic relationships (SKR) of pyrrolopiperidinone acetic acids as CRTh2 antagonists.

Pyrrolopiperidinone acetic acids (PPAs) were identified as highly potent CRTh2 receptor antagonists. In addition, many of these compounds displayed slow-dissociation kinetics from the receptor. Structure-kinetic relationship (SKR) studies allowed optimisation of the kinetics to give potent analogues with long receptor residence half-lives of up to 23 h. Low permeability was a general feature of this series, however oral bioavailability could be achieved through the use of ester prodrugs.

A novel inhaled Syk inhibitor blocks mast cell degranulation and early asthmatic response

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.

2-(1H-Pyrazol-4-yl)acetic acids as CRTh2 antagonists

High throughput screening identified the pyrazole-4-acetic acid substructure as CRTh2 receptor antagonists. Optimisation of the compounds uncovered a tight SAR but also identified some low nanomolar inhibitors.

2-(1H-Pyrazol-1-yl)acetic acids as chemoattractant receptor-homologous molecule expressed on Th2 lymphocytes (CRTh2) antagonists

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.

Pharmacological characterization of CRTh2 antagonist LAS191859: Long receptor residence time translates into long-lasting in vivo efficacy.

The chemoattractant receptor-homologous molecule expressed on T-helper type 2 cells (CRTh2) is a G protein-coupled receptor expressed on the leukocytes most closely associated with asthma and allergy like eosinophils, mast cells, Th2-lymphocytes and basophils. At present it is clear that CRTh2 mediates most prostaglandin D2 (PGD2) pro-inflammatory effects and as a result antagonists for this receptor have reached asthma clinical studies showing a trend of lung function improvement. The challenge remains to identify compounds with improved clinical efficacy when administered once a day. Herein we described the pharmacological profile of LAS191859, a novel, potent and selective CRTh2 antagonist. In vitro evidence in GTPγS binding studies indicate that LAS191859 is a CRTh2 antagonist with activity in the low nanomolar range. This potency is also maintained in cellular assays performed with human eosinophils and whole blood. The main differentiation of LAS191859 vs other CRTh2 antagonists is in its receptor binding kinetics. LAS191859 has a residence time half-life of 21h at CRTh2 that translates into a long-lasting in vivo efficacy that is independent of plasma levels. We believe that the strategy behind this compound will allow optimal efficacy and posology for chronic asthma treatment.

Structure–activity relationships (SAR) and structure–kinetic relationships (SKR) of bicyclic heteroaromatic acetic acids as potent CRTh2 antagonists II: Lead optimization

Extensive structure-activity relationship (SAR) and structure-kinetic relationship (SKR) studies in the bicyclic heteroaromatic series of CRTh2 antagonists led to the identification of several molecules that possessed both excellent binding and cellular potencies along with long receptor residence times. A small substituent in the bicyclic core provided an order of magnitude jump in dissociation half-lives. Selected optimized compounds demonstrated suitable pharmacokinetic profiles.

Structure–activity relationships (SAR) and structure–kinetic relationships (SKR) of bicyclic heteroaromatic acetic acids as potent CRTh2 antagonists I

A knowledge-based design strategy led to the discovery of several new series of potent and orally bioavailable CRTh2 antagonists where a bicyclic heteroaromatic ring serves as the central core. Structure-kinetic relationships (SKR) opened up the possibility of long receptor residence times.

4-Amino-7,8-dihydro-1,6-naphthyridin-5(6H)-ones as Inhaled Phosphodiesterase Type 4 (PDE4) Inhibitors: Structural Biology and Structure–Activity Relationships

Rational design of a novel template of naphthyridinones rapidly led to PDE4 inhibitors with subnanomolar enzymatic potencies. X-ray crystallography confirmed the binding mode of this novel template. We achieved compounds with double-digit picomolar enzymatic potencies through further structure-based design by targeting both the PDE4 enzyme metal-binding pocket and occupying the solvent-filled pocket. A strategy for lung retention and long duration of action based on low aqueous solubility was followed. In vivo efficacies were measured in a rat lung neutrophilia model by suspension microspray and dry powder administration. Suspension microspray of potent compounds showed in vivo efficacy with a clear dose-response. Despite sustained lung levels, dry powder administration performed much less well and without proper dose-response, highlighting clear differences between the two formulations. This indicates a deficiency in the low aqueous solubility strategy for long duration lung efficacy.

Characterization of the chloroquine-induced mouse model of pruritus using an automated behavioural system

Pruritus is a major symptom of several dermatological diseases but has limited therapeutic options available. Animal models replicating the pathophysiology of pruritus are needed to support the development of new drugs. Induction of pruritus by chloroquine (CQ) in mice is widely used, although, as with similar models, it has low throughput and does not distinguish between antipruritic effects and confounding factors such as sedation. To overcome these issues, we incorporated into the model an automated system that measures both scratching and locomotor behaviour simultaneously. We combined this system with the determination of CQ levels in different tissues to understand the impact of the route of CQ administration on the pruritogenic response. We concluded that whereas oral CQ does not induce pruritus due to insufficient skin levels, the bell‐shaped curve of pruritus observed following subcutaneous administration is due to toxicity at high doses. We validated the model with several drugs currently used in humans: nalfurafine, aprepitant, cyproheptadine and amitriptyline. By comparing the effects of the drugs on both scratching and locomotor activity, we concluded that nalfurafine and aprepitant can exhibit efficacy at doses devoid of central effects, whereas central effects drove the efficacy of the other two drugs. This was further confirmed using non‐brain‐penetrant drugs. Moreover, as anticipated, anti‐inflammatory drugs showed no efficacy. In conclusion, the use of an automated integrated behavioural assessment in CQ‐induced pruritus makes the assay suitable for screening purposes and allows for a correct interpretation of the antipruritic effect of the compounds evaluated.