Pharmacology of orismilast, a potent and selective PDE4 inhibitor.

Background: There remains an unmet need for oral medications that are safe and efficacious for long-term management of chronic inflammatory skin diseases (CISD). Inhibition of phosphodiesterase 4 (PDE4) can modulate a broad range of pro-inflammatory cytokines that play a major role in CISD pathogenesis. Orismilast is a second generation PDE4 inhibitor in clinical development for CISD treatment.

Design and characterization of matrix metalloproteinase-responsive hydrogels for the treatment of inflammatory skin diseases.

Enzyme-responsive hydrogels, formed by step growth photopolymerization of biscysteine peptide linkers with alkene functionalized polyethylene glycol, provide interesting opportunities as biomaterials and drug delivery systems. In this study, we developed stimuli-responsive, specific, and cytocompatible hydrogels for delivery of anti-inflammatory drugs for the treatment of inflammatory skin diseases. We designed peptide linkers with optimized sensitivity towards matrix metalloproteinases, a family of proteolytic enzymes overexpressed in the extracellular matrix of the skin during inflammation.

Convergent total synthesis of (+)-calcipotriol: A scalable, modular approach to vitamin D analogs.

A convergent approach for the total synthesis of calcipotriol (brand name: Dovonex), a proven vitamin D analog used for the treatment of psoriasis, and medicinally relevant synthetic analogs is described. A complete approach, not wedded to semisynthesis, toward both the A-ring and CD-ring is reported. From a retrosynthetic standpoint, hidden symmetry within the decorated A-ring is disclosed, which allowed for scalable quantities of this advanced intermediate.

Macrolide Inspired Macrocycles as Modulators of the IL-17A/IL-17RA Interaction.

Interleukin 17 (IL-17) cytokines promote inflammatory pathophysiology in many autoimmune diseases, including psoriasis, multiple sclerosis, rheumatoid arthritis, and inflammatory bowel disease. Such broad involvement of IL-17 in various autoimmune diseases makes it an ideal target for drug discovery. Psoriasis is a chronic inflammatory disease characterized by numerous defective components of the immune system.

Discovery and Early Clinical Development of Isobutyl 1-[8-Methoxy-5-(1-oxo-3-isobenzofuran-5-yl)-[1,2,4]triazolo[1,5-]pyridin-2-yl]cyclopropanecarboxylate (LEO 39652), a Novel "Dual-Soft" PDE4 Inhibitor for Topical Treatment of Atopic Dermatitis.

We describe the design of a novel PDE4 scaffold and the exploration of the dual-soft concept to reduce systemic side effects via rapid elimination: introducing ester functionalities that can be inactivated in blood as well as by the liver (dual-soft) while being stable in human skin. Compound was selected as a clinical candidate as it was potent and rapidly degraded by blood and liver to inactive metabolites and because in preclinical studies it showed high exposure at the target organ: the skin. Preclinical and clinical data are presented confirming the value of the dual-soft concept in reducing systemic exposure.

Detection of fumarate-glutathione adducts in the portal vein blood of rats: evidence for rapid dimethylfumarate metabolism.

Dimethylfumarate (DMF), the essential ingredient of the drug product Fumaderm®, is used to treat psoriasis with a recognized favorable long-term safety profile. Interestingly, the mode of action and the pharmacokinetics of DMF in psoriasis or multiple sclerosis are not fully explored. It is known that DMF as an α,β-unsaturated carboxylic acid ester forms an adduct with the antioxidant glutathione in vitro via a Michael-type addition within a very short period of time.

Mitogen- and stress-activated protein kinase 1 is activated in lesional psoriatic epidermis and regulates the expression of pro-inflammatory cytokines.

Mitogen- and stress-activated protein kinase 1 (MSK1) is a downstream target of both the p38 and extracellular signal-regulated kinase 1/2 (ERK1/2) mitogen-activated protein kinases (MAPKs). MSK1 stimulates transcription of different pro-inflammatory genes through activation of transcription factors. The purpose of this study was to investigate the expression and activation of MSK1 in lesional psoriatic skin and its role in cytokine production in cultured normal human keratinocytes.

Protein expression of TNF-alpha in psoriatic skin is regulated at a posttranscriptional level by MAPK-activated protein kinase 2.

Alterations in specific signal transduction pathways may explain the increased expression of proinflammatory cytokines seen in inflammatory diseases such as psoriasis. We reveal increased TNF-alpha protein expression, but similar TNF-alpha mRNA levels, in lesional compared with nonlesional psoriatic skin, demonstrating for the first time that TNF-alpha expression in lesional psoriatic skin is regulated posttranscriptionally. Increased levels of activated MAPK-activated protein kinase 2 (MK2) together with increased MK2 kinase activity were found in lesional compared with nonlesional psoriatic skin.

Synthesis and structure-activity relationship of aminobenzophenones. A novel class of p38 MAP kinase inhibitors with high antiinflammatory activity.

We wish to report the synthesis and structure-activity relationship (SAR) of a series of 4-aminobenzophenones, as a novel compound class with high antiinflammatory activity. Our initial lead, (4-[(2-aminophenyl)amino]phenyl)(phenyl)methanone (3), was systematically optimized and resulted in compounds that potently inhibited the release of the proinflammatory cytokines IL-1beta and TNF-alpha in human peripheral blood mononuclear cells stimulated by LPS. One of the most potent compounds, among others, was (4-[(2-aminophenyl)amino]-2-chlorophenyl)(2-methylphenyl)methanone (45) with IC(50) values of 14 and 6 nM for the inhibition of IL-1beta and TNF-alpha, respectively.