Discovery and characterization of NVP-QAV680, a potent and selective CRTh2 receptor antagonist suitable for clinical testing in allergic diseases.

Optimization of a 7-azaindole-3-acetic acid CRTh2 receptor antagonist chemotype derived from high throughput screening furnished a highly selective compound NVP-QAV680 with low nM functional potency for inhibition of CRTh2 driven human eosinophil and Th2 lymphocyte activation in vitro. The molecule exhibited good oral bioavailability in the rat, combined with efficacy in rodent CRTh2-dependent mechanistic and allergic disease models and was suitable for clinical development.

Topical treatment of Basal cell carcinomas in nevoid Basal cell carcinoma syndrome with a smoothened inhibitor.

Basal cell carcinoma (BCC) is a distinctive manifestation in nevoid basal cell carcinoma syndrome (NBCCS) patients. Both inherited and acquired mutations of patched 1 (PTCH1), a tumor-suppressor gene controlling the activity of Smoothened (SMO), are the primary cause of the constitutive activation of the Hedgehog (HH) pathway, leading to the emergence of BCCs in NBCCS. LDE225, a distinct, selective antagonist of SMO, showed potent inhibition of basaloid tumor nest formation and mediated regression of preformed basaloid tumors in organ cultures of skin derived from Ptch1 heterozygous knockout mice. In a double-blind, randomized, vehicle-controlled, intraindividual study, a total of 8 NBCCS patients presenting 27 BCCs were treated twice daily with 0.75% LDE225 cream or vehicle for 4 weeks. Application of 0.75% LDE225 cream was well tolerated and showed no skin irritation. Of 13 LDE225-treated BCCs, 3 showed a complete, 9 a partial, and only 1 no clinical response. Except for one partial response, the vehicle produced no clinical response in any of the 14 treated BCCs. Treatment with 0.75% LDE225 cream in NBCCS patients was very well tolerated and caused BCC regression, thus potentially offering an attractive therapeutic alternative to currently available therapies for this indication.JID JOURNAL CLUB ARTICLE: For questions, answers, and open discussion about this article, please go to http://www.nature.com/jid/journalclub.

Pimecrolimus permeates less than tacrolimus through normal, inflamed, or corticosteroid-pretreated skin.

The permeabilities of normal human and normal, inflamed, or corticosteroid (CS) pretreated skin of young domestic pigs for pimecrolimus and tacrolimus were compared in vitro, using Franz-type diffusion cells. The test articles were either used as 1.0% solutions or as the marketed formulations (Elidel 1% cream, Protopic 0.1%, and 0.03% ointment). In normal human skin, the permeation rate of pimecrolimus from the 1% cream was about sixfold lower than that of tacrolimus from 0.1% ointment and by a factor of 4.3 lower compared with tacrolimus from Protopic 0.03%. In pigs, sodium laurylsulfate-induced irritant contact dermatitis resulted in significantly faster skin permeation of both drugs from applied solutions. The permeation rate for pimecrolimus was lower than that for tacrolimus. Thus, at 24 h, pimecrolimus concentrations in the receptor fluid were 2.8-fold lower than the tacrolimus levels. Compared with normal porcine skin, permeation of drugs through hydrocortisone (1.0%)-, mometasone (0.1%)-, or clobetasol-17-butyrate (0.05%)-pretreated skin was increased by factors of 3.6 (pimecrolimus, applied as 1% cream) and 1.7 (tacrolimus, applied as 0.1% ointment). In normal pig skin, the permeation rate of tacrolimus was found to be 11.2 times higher than that of pimecrolimus and 3.5- to 7.1-fold higher in CS-pretreated skin, independent of the potency of the CSs. The present in vitro data suggest that in patients with acute skin inflammation or after therapy with topical CSs, percutaneous absorption and, as a consequence, systemic drug exposure will be lower with Elidel 1% cream as compared with Protopic 0.1% and 0.03% ointment.

Percutaneous absorption of drugs used in atopic eczema: pimecrolimus permeates less through skin than corticosteroids and tacrolimus.

For treatment of skin diseases with topical drugs, penetration of the agents into the relevant layers of the skin is required. Permeation through the skin should, however, be kept to a minimum, in order to avoid the risk of systemic side effects. Here we compared the in vitro skin penetration and permeation of two novel drugs used in the therapy of atopic eczema (pimecrolimus and tacrolimus) and three representative corticosteroids (betamethasone-17-valerate, clobetasol-17-propionate, and diflucortolon-21-valerate). Drug concentrations of pimecrolimus and corticosteroids in human skin were found to be in the same order of magnitude. Permeation of pimecrolimus through human skin was, however, lower by factors of 70-110 as compared to the steroids. When pimecrolimus was compared with tacrolimus in human, pig, or rat skin, similar concentrations of the two compounds were measured in the skin, whereas permeation of pimecrolimus through skin was consistently lower by factors of 9-10. Lipophilicity was found to be highest for pimecrolimus, its octanol-water distribution coefficient being higher by factors of 8 and 25-450 than that of tacrolimus and the corticosteroids, respectively. The low permeation of pimecrolimus may be explained by its higher lipophilicity (compared to tacrolimus and the corticosteroids) and higher molecular weight (compared to steroids). In conclusion, pimecrolimus appears to have a favourable skin penetration/permeation profile, featuring a low degree of percutaneous absorption.