Rational Drug Design of Topically Administered Caspase 1 Inhibitors for the Treatment of Inflammatory Acne

被引：14

作者：

Fournier, Jean-Francois ^{[1
]}

Clary, Laurence ^{[1
]}

Chambon, Sandrine ^{[1
]}

Dumais, Laurence ^{[1
]}

Harris, Craig Steven ^{[1
]}

Millois, Corinne ^{[1
]}

Pierre, Romain ^{[1
]}

Talano, Sandrine ^{[1
]}

Thoreau, Etienne ^{[1
]}

Aubert, Jerome ^{[1
]}

Aurelly, Michele ^{[1
]}

Bouix-Peter, Claire ^{[1
]}

Brethon, Anne ^{[2
]}

Chantalat, Laurent ^{[1
]}

Christin, Olivier ^{[1
]}

Comino, Catherine ^{[1
]}

El-Bazbouz, Ghizlane ^{[1
]}

Ghilini, Anne-Laurence ^{[1
]}

Isabet, Tatiana ^{[3
]}

Lardy, Claude ^{[2
]}

Luzy, Anne-Pascale ^{[1
]}

Mathieu, Celine ^{[1
]}

Mebrouk, Kenny ^{[1
]}

Orfila, Danielle ^{[1
]}

Pascau, Jonathan ^{[1
]}

Reverse, Kevin ^{[1
]}

Roche, Didier ^{[2
]}

Rodeschini, Vincent ^{[2
]}

Hennequin, Laurent Francois ^{[1
]}

机构：

[1] Nestle Skin Hlth R&D, 2400 Route Colles,BP 87, F-06902 Sophia Antipolis, France

[2] Edelris, 115 Ave Lacassagne, F-69003 Lyon, France

[3] LOrme Merisiers, Synchrotron Soleil, BP 48, F-91192 Gif Sur Yvette, France

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2018年 / 61卷 / 09期

关键词：

INTERLEUKIN-1-BETA CONVERTING-ENZYME; MEDICINAL CHEMISTRY; IN-VIVO; SOLUBILITY; DISCOVERY; PREDICTION; SKIN; PERMEABILITY; DESCRIPTORS; PRINCIPLES;

D O I：

10.1021/acs.jmedchem.8b00067

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The use of an interleukin beta antibody is currently being investigated in the clinic for the treatment of acne, a dermatological disorder affecting 650M persons globally. Inhibiting the protease responsible for the cleavage of inactive pro-IL1 beta into active IL-1 beta, caspase-1, could be an alternative small molecule approach. This report describes the discovery of uracil 20, a potent (38 nM in THP1 cells assay) caspase-1 inhibitor for the topical treatment of inflammatory acne. The uracil series was designed according to a published caspase-1 pharmacophore model involving a reactive warhead in P1 for covalent reversible inhibition and an aryl moiety in P4 for selectivity against the apoptotic caspases. Reversibility was assessed in an enzymatic dilution assay or by using different substrate concentrations. In addition to classical structure activity-relationship exploration, topical administration challenges such as phototoxicity, organic and aqueous solubility, chemical stability in solution, and skin metabolic stability are discussed and successfully resolved.

引用

页码：4030 / 4051

页数：22

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