Introduction
For more than 25 years, p38 mitogen activated protein kinase (p38
MAP-kinase) represents a pharmacological target in various autoimmune
diseases such as rheumatoid arthritis, psoriasis and Crohn’s.[1–4]
These autoimmune conditions require alternative therapeutic approaches
(either as mono-therapy or as add-on therapy combined with drugs like
methotrexate, prednisone, and biologicals) to overcome problems such as
side effects and the development of drug resistance.[5] p38
MAP-kinase inhibition has been claimed as a promising therapeutic
approach for the chronic inflammatory component of neurodegenerative
diseases, such as Alzheimer’s disease.[6] Activated p38 MAP-kinase
activates downstream transcription factors, ultimately resulting in the
release of different pro-inflammatory cytokines such as
TNFα,
IL-1β and IL-6.[7] The MAP-kinase inflammatory pathway can be
activated by different receptors including Toll-Like receptors (TLR),
cytokine receptors and G-protein-coupled receptors by a variety of
stimuli such as bacterial components, superantigen, cytokines, amyloid
β-induced cell dysfunction, and heat and osmotic shock.[6, 8] Four
subtypes of p38 MAP-kinase have been described (α, β, у, δ), of which
p38α is the most relevant subtype involved in the process of
inflammation.[9] p38α is expressed in almost all cell types,
including inflammatory cells such as monocytes and lymphocytes.[10]In vitro inhibition of p38α MAP-kinase decreases the release of
pro-inflammatory cytokines after stimulation with lipopolysaccharide
(LPS), a bacterial endotoxin activating the TLR4 pathway, demonstrating
the potential therapeutic benefit of inhibition of p38α MAP-kinase in
inflammatory conditions.[11, 12] Different p38 MAP-kinase inhibitors
have been under preclinical or clinical development, but were halted due
to safety concerns or lack of efficacy.[13] Drug development
strategies aiming for increased selectivity and potency resulted in the
development of the imidazole derivatives, competitive inhibitors at the
ATP-binding site of the kinase. Modifications on the imidazole scaffold
yielded a large number of potent p38α MAP kinase inhibitors.[14]
Recent reviews describe p38 MAP-kinase as potential therapeutic target
for inflammatory conditions as asthma.[15]
The synthetic compound Org 48775-0 is a potent and highly selective oral
p38α/β MAP-kinase inhibitor (Figure 1). On a panel of more than 100
human kinases, Org 48775-0 was shown to selectively inhibit p38α and β
kinases. In vitro data demonstrated that Org 48775-0 potently
reduces the activation of the p38α signaling pathway in LPS-stimulated
immune cells. In mouse models of acute and chronic inflammation a
strong, dose-dependent effect of Org 48775-0 was shown. Org 48775-0
reduced LPS-induced TNFα production in mice and inhibited disease
progression in collagen-induced arthritic mice. Org 48762-0, a closely
related compound, potently inhibited p38a kinase activity and bone
damage in a murine model of collagen-induced arthritis.[16]
In this first-in-human single ascending dosing (SAD) and multiple
ascending dosing (MAD) study, we investigated the safety, tolerability,
pharmacokinetics (PK) and pharmacodynamics (PD) of Org 48775-0 in a in
healthy volunteers. In addition, the effect of food on the PK/PD
characteristics of Org 48775-0 was evaluated, and potential differences
in drug effect between genders were studied. PK and PD parameters of Org
48775-0 were compared between healthy males and postmenopausal females:
the prevalence of autoimmune diseases is higher in females than in males
[17–19], and gender differences were observed for Org48775-0
pharmacokinetics in preclinical experiments. To account for a potential
food effect on drug absorption, as may happen after meals high in fat
and calorie content [20], the effect of a standardized fat meal on
the PK and PD of Org 48775-0 was evaluated.