Design of a Supersoft Topical JAK Inhibitor, Which Is Effective in Human Skin but Rapidly Deactivated in Blood.

We describe the discovery and characterization of the supersoft topical JAK inhibitor , which is potent in biochemical and cellular assays as well as in human skin models. In blood, the neutral ester is rapidly hydrolyzed ( ∼ 6 min) to the corresponding charged carboxylic acid exhibiting >30-fold reduced permeability. Consequently, acid does not reach the intracellular JAK kinases and is inactive in cellular assays and in blood.

Novel Concept for Super-Soft Topical Drugs: Deactivation by an Enzyme-Induced Switch into an Inactive Conformation.

We present a novel concept for the design of supersoft topical drugs. Enzymatic cleavage of the carbonate ester of the potent pan Janus kinase (JAK) inhibitor releases hydroxypyridine . Due to hydroxypyridine-pyridone tautomerism, undergoes a rapid conformational change preventing the compound to assume the bioactive conformation required for binding to JAK kinases.

Discovery and Characterization of the Topical Soft JAK Inhibitor CEE321 for Atopic Dermatitis.

The JAK kinases JAK1, JAK2, JAK3, and TYK2 play key roles in cytokine signaling. Activation of the JAK/STAT pathways is linked to many diseases involving the immune system, including atopic dermatitis. As systemic JAK inhibitor pharmacology is associated with side effects, topical administration to the skin has been considered to locally restrict the site of action.

Requirement of Mucosa-Associated Lymphoid Tissue Lymphoma Translocation Protein 1 Protease Activity for Fcγ Receptor-Induced Arthritis, but Not Fcγ Receptor-Mediated Platelet Elimination, in Mice.

Objective: Fcγ receptors (FcγR) play important roles in both protective and pathogenic immune responses. The assembly of the CBM signalosome encompassing caspase recruitment domain-containing protein 9, B cell CLL/lymphoma 10, and mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT-1) is required for optimal FcγR-induced canonical NF-κB activation and proinflammatory cytokine release. This study was undertaken to clarify the relevance of MALT-1 protease activity in FcγR-driven events and evaluate the therapeutic potential of selective MALT-1 protease inhibitors in FcγR-mediated diseases.

Special ergolines efficiently inhibit the chemokine receptor CXCR3 in blood.

The structure-activity relationship of highly potent special ergolines which selectively block the chemokine receptor CXCR3 is reported. The most potent compounds showed IC(50) values below 10nM in both ligand binding and Ca(2+)-mobilization assays. However, these compounds were poorly active in an assay that measures receptor occupancy in blood.

Targeting the CXCR4-CXCL12 axis mobilizes autologous hematopoietic stem cells and prolongs islet allograft survival via programmed death ligand 1.

Antagonism of CXCR4 disrupts the interaction between the CXCR4 receptor on hematopoietic stem cells (HSCs) and the CXCL12 expressed by stromal cells in the bone marrow, which subsequently results in the shedding of HSCs to the periphery. Because of their profound immunomodulatory effects, HSCs have emerged as a promising therapeutic strategy for autoimmune disorders. We sought to investigate the immunomodulatory role of mobilized autologous HSCs, via target of the CXCR4-CXL12 axis, to promote engraftment of islet cell transplantation.

Special ergolines are highly selective, potent antagonists of the chemokine receptor CXCR3: discovery, characterization and preliminary SAR of a promising lead.

The special ergoline 1 is a highly potent, selective antagonist of the chemokine receptor CXCR3. The surprising selectivity of this LSD-related compound can be explained by different electronic and steric properties of the ergoline core structure caused by the urea portion of the molecule. Discovery, biopharmaceutical properties and first derivatives of this promising lead compound are discussed.

Reduced cardiac side-effect potential by introduction of polar groups: discovery of NIBR-1282, an orally bioavailable CCR5 antagonist which is active in vivo.

Introduction of polar groups in a series of potent CCR5 antagonists which are very likely to adversely affect the conduction system in the heart led to the identification of NIBR-1282 which did not show adverse effects when tested in an isolated rabbit heart ex vivo model. Administration of NIBR-1282 in combination with a non-efficacious dose of CsA led to significant prolongation of kidney allograft survival in cynomolgus monkeys.

Orally bioavailable competitive CCR5 antagonists.

The chemokine receptor CCR5 plays an important role in inflammatory and autoimmune disorders as well as in transplant rejection by affecting the trafficking of effector T cells and monocytes to diseased tissues. Antagonists of CCR5 are believed to be of potential therapeutic value for the disorders mentioned above and HIV infection. Here we report on the structure-activity relationship of a new series of highly potent and selective competitive CCR5 antagonists.

Interferon-gamma plays a nonredundant role in mediating T cell-dependent outward vascular remodeling of allogeneic human coronary arteries.

Vascular remodeling (change in vessel diameter) rather than intimal hyperplasia is the most important predictor of luminal loss in immune-mediated arterial injury, yet little is known about its mechanisms. Here, we show that outward vascular remodeling and intimal thickening, two manifestations of arteriosclerosis with opposing effects on luminal size, result from immune effector mechanisms that are T-cell dependent and interferon (IFN)-gamma mediated. In our in vivo model of human coronary artery injury by allogeneic peripheral blood mononuclear cells, both processes occur concurrently and are characterized by T-cell infiltrates with a predominantly IFN-gamma-producing cytokine profile.