Inflammatory Bowel Disease (IBD) includes conditions where the patients suffer from inflammation in the gastrointestinal (GI)-tract. Several of those are considered to be of chronic nature, e.g. Crohn's disease and ulcerative colitis, and the medical need is large. The patients suffer from fevers, pain, diarrhea or constipation and in addition hemorrhagic stool. Treatment is constrained to symptom relief, inflammatory suppression and in severe cases surgery and which all current treatment are linked to relatively severe side effects. Anti-inflammatory treatments with oral gluco-corticoid receptor (GCR) agonists (e.g. Budesonide, Prednisolone or Fluticazone) can cause diabetes, Cushing's syndrome, skin defects. In addition GCR agonist treatment suppresses life saving immuno-activation upon infection by virus, bacteria or other pathogenic microbes, which further reduces patient quality of life and increases risk for secondary disease. Non-Steroidal Anti-Inflammatory Drugs (NSAID) and antibiotics (e.g. 5-ASA, Sulfasalazine, and Metronidazole) are also commonly used, however with limited effect. Similar reasoning as above is also relevant for other inflammatory diseases such as asthma and Chronic Obstructive Pulmonary Disease (COPD). Thus, there is a great need for more effective anti-inflammatory treatments with less or preferably no side effects.
The nuclear hormone receptors (NHRs) comprise a series of soluble protein complexes that upon ligand modulation and co-factor complexation translocate to the cellular nucleus with subsequent binding to specific DNA regions. Such binding induces or reduces protein expression cascades and, for several NHRs, immunoactivation or deactivation has been implicated. For example, Oestrogen receptors (Steffan et al, 2006), the Liver X Receptor (LXR) (Tontonoz et al, US2004/0259948; Zelcer & Tontonoz, 2006) and the Peroxisome Proliferator Activated Receptor (PPAR)-α, γ and/or δ, (Desreumaux et al, 2001; Tanaka et al, 2001; Lewis et al, 2001; Patel et al; 2003) have all been suggested to exert such immuno-modulatory effects via small molecular modulators. NHRs are in general multi-potent in the sense that they regulate several profound physiological events, either simultaneously or sequentially, depending on the cell type or tissue in which the modulation is accomplished. This might also be the reason for unwanted effects from these NHR modulators, which are in parallel with the mechanism related side effects observed with the GCR modulators.
The regulation of inflammatory responses by PPARs have been suggested to involve the trans-repression of inflammatory gene activation by interfering with several signalling pathways of the transcription factors NFkB, STAT-1, NFAT and AP-1. As a result of this interaction, a number of down-streams pathways are affected. These includes the downregulation of pro-inflammatory cytokines (e.g., IL-1β, IL-6, TNF) or chemokines (e.g., MCP-1, IL-8), decrease expression of adhesion molecules (e.g., V-CAM) resulting in reduced leukocyte recruitment. Other anti-inflammatory effects include the decreased expression of oxidative stress markers (e.g., iNOS, COX-2), the repressed expression of extra cellular matrix components (e.g., MMPs, TGF-β), as well as induced apoptosis in a variety of cell types (Belvisi M et al., 2006; Duboquoy L et al., 2006; Cunard R 2005). In addition to its anti-inflammatory action, PPARs have also been suggested to have anti-proliferative properties, possibly as a result of induction of cell cycle arrest and/or apoptosis (Galli A et al., 2006).
Compounds delivered orally initially expose the GI-tract and an inhaled compound the respiratory organs when administered to patients. Given the above reasoning it would be advantageous, for a patient with GI inflammation, for a compound to have properties such that it exposes the GI tract but is designed to be eliminated or metabolized before it reaches cells, tissues or body compartments where it can induce unwanted effects. A method to accomplish this has been introduced by Bodor and co-workers (Bodor et al, 1995; Bodor & Buchwald, 2006; Bodo & Bodor, WO 9200988), who named it “soft-drugs”, meaning a drug that exerts its pharmacological or medicinal effects during a controlled time frame in a controlled compartment, and thereafter is “soft” in the sense that it is predestined to elimination by metabolism in a predicted way.
The definition of the term “soft drug” varies. In this patent application, the definition of the term “soft drug” is a chemical compound that exerts its activity in the target organ, and subsequent inactivation or alteration by metabolism is such that receptor modulation within other compartments (e.g. systemic compartments) is excluded and unwanted effects and/or side effects that are disadvantageous, or of no use, for the patient is reduced.
US 2003/0236227 discusses the use of soft drugs for the treatment of diabetes, hyperlipidemia, hypercholesterolemia, and atherosclerosis. However, these soft drugs have activity in the systemic compartment, and thus they do not fall within the definition of the term “soft drugs” in this patent application. Further, US 2003/0236227 is silent about compounds having anti-inflammatory properties.
As discussed above, there remains a need for compounds having anti-inflammatory properties. In particular, there is a need for compounds with anti-inflammatory effect and having the property of being locally active in the target organ with little or no effect in other compartments (e.g. systemic compartments).
Accordingly, we hereby provide compounds with anti-inflammatory properties which are believed to act according to the definition of the term “soft drug” in the present patent application.
The term “PPAR modulator” as used herein, refers to the ability of a compound to modulate the biological activity of PPARα and/or PPARγ and/or PPARδ via increase or decrease of the function and/or expression of PPARα and/or PPARγ and/or PPARδ, where PPARα and/or PPARγ and/or PPARδ function may include transcription regulatory activity and/or protein-binding. Modulation may occur in vitro or in vivo. Modulation, as described herein, includes antagonism, agonism, partial antagonism and/or partial agonism of a function or characteristic associated with PPARα and/or PPARγ and/or PPARδ, either directly or indirectly, and/or the upregulation or downregulation of PPARα and/or PPARγ and/or PPARδ expression, either directly or indirectly. More specifically, such a PPAR modulator either enhances or inhibits the biological activities of PPAR via the function and/or expression of PPAR. If such a modulator partially or completely enhances the biological activities of PPAR via the function and/or expression of PPAR, it is a partial or full PPAR agonist, respectively. It is the object of the present invention to provide PPAR modulators. Another object of this invention is to provide PPAR modulator compounds being PPAR agonists.
To aid understanding the terms “local” and “systemic” compartments, for oral administration the local compartment is the GI tract (i.e. gastrointestinal tract); when a compound has passed beyond/through the liver it has reached the systemic compartment. For inhaled compounds the lung is the local compartment, and beyond the lung is the systemic compartment.
By systemic compartment we mean any tissue or organ that an administrated compound reaches after it has passed beyond/through another tissue or organ in which some (e.g. 90%, but also including 100%) elimination or metabolism of the compound as occurred.
An aim with PPAR soft drugs for IBD should be to not accept predicted human systemic exposure higher than a factor (e.g. 10) below a corresponding exposure that would give an expected pharmacological effect in dyslipidemic patients.
It should be noted that to show activity in the specific Test Methods described herein, the PPAR modulator compound must bind to the ligand binding domain of the PPAR and recruit one or more of the nuclear hormone receptor co-factors present in the U-2 OS cell-based method described herein. The compounds of this invention that form an PPAR-modulator compound-complex may recruit at least one or more of the other >80 known different nuclear hormone receptor cofactors in any other cell-based method, prepared and assayed according to known procedures. Compounds according to Formula I, XI, CI and MI, that do not recruit any of the co-factors present in the in cell-based method described herein, are however anticipated to bind to PPAR and the PPAR-modulator compound-complex so formed will recruit at least one or more of the other >80 known different nuclear receptor co-factors present in other cellular systems. The PPAR modulator compound-complex may also displace co-repressors, with simultaneous recruitment of a co-activator or alternatively displace a co-repressor without co-activator recruitment, leading to partial activation of certain PPAR regulated genes. Peptides derived from any of these other nuclear hormone receptor co-factors may be similarly prepared and assayed according to known procedures.
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