Compounds and methods for treating inflammatory and fibrotic disorders

Abstract

Disclosed are compounds and methods for treating inflammatory and fibrotic disorders, including methods of modulating a stress activated protein kinase (SAPK) system with an active compound, wherein the active compound exhibits low potency for inhibition of the p38 MAPK; and wherein the contacting is conducted at a SAPK-modulating concentration that is at a low percentage inhibitory concentration for inhibition of the p38 MAPK by the compound. Also disclosed are derivatives and analogs of pirfenidone, useful for modulating a stress activated protein kinase (SAPK) system.

Mederski et al., Tetrahedron (1999), 55(44), 12757-12770.*

Azuma et al., “A placebo control and double blind phase II clinical study of pirfenidone in patients with idiopathic pulmonary fibrosis in Japan”, Am J Respir Crit Care Med., 165:A729 (2002).

Badger, et al., “Pharmacological profile of SB 203580, a selective inhibitor of cytokine suppressive binding protein/p38 kinase, in animal models of arthritis, bone resorption, endotoxin shock and immune function”, J. Pharmacol. Exp. Ther. 279:1453-61 (1996).

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the priority benefit under 35 USC §119(e) of U.S. Provisional Application No. 61/058,436, filed Jun. 3, 2008 and U.S. Provisional Application No. 61/074,446, filed Jun. 20, 2008, each of which is incorporated by reference in its entirety.

BACKGROUND

1. Field of the Invention

This invention relates to compounds and methods useful in treating various inflammatory and fibrotic conditions, including those associated with enhanced activity of kinase p38.

2. Background of the Invention

A large number of chronic and acute conditions have been recognized to be associated with perturbation of the inflammatory response. A large number of cytokines participate in this response, including IL-1, IL-6, IL-8 and TNFα. It appears that the activity of these cytokines in the regulation of inflammation may be associated with the activation of an enzyme on the cell signaling pathway, a member of the MAP kinase family generally known as p38 and also known as SAPK, CSBP and RK.

Several inhibitors of p38, such as NPC 31169, SB239063, SB203580, FR-167653, and pirfenidone have been tested in vitro and/or in vivo and found to be effective for modulating inflammatory responses.

There continues to be a need for safe and effective drugs to treat various inflammatory conditions such as inflammatory pulmonary fibrosis.

SUMMARY

Disclosed herein are compounds of formula I

##STR00001##
wherein M is N or CR¹; A is N or CR²; L is N or CR³; B is N or CR⁴; E is N or CX⁴; G is N or CX³; J is N or CX²; K is N or CX¹; a dashed line is a single or double bond, except when B is CR⁴, then each dashed line is a double bond;
R¹ is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, cyano, sulfonamido, halo, aryl, alkenylenearyl, and heteroaryl;
R² is selected from the group consisting of hydrogen, alkyl, haloalkyl, halo, cyano, aryl, alkenyl, alkenylenearyl, heteroaryl, haloalkylcarbonyl, cycloalkyl, hydroxylalkyl, sulfonamido, and cycloheteroalkyl or R² and R¹ together form an optionally substituted 5-membered nitrogen-containing heterocyclic ring;
R³ is selected from the group consisting of hydrogen, aryl, alkenylenearyl, heteroaryl, alkyl, alkenyl, haloalkyl, amino, and hydroxy;
R⁴ is selected from the group consisting of hydrogen, alkyl, haloalkyl, cyano, alkoxy, aryl, alkenyl, alkenylenearyl, and heteroaryl; and
X¹, X², X³, X⁴, and X⁵ are independently selected from the group consisting of hydrogen, alkyl, alkenyl, halo, hydroxy, amino, aryl, cycloalkyl, thioalkyl, alkoxy, haloalkyl, haloalkoxy, alkoxyalkyl, cyano, aldehydo, alkylcarbonyl, amido, haloalkylcarbonyl, sulfonyl, and sulfonamide, or X² and X³ together form a 5- or 6-membered ring comprising —O(CH₂)_nO—, wherein n is 1 or 2,
with the proviso that when all of A, B, E, G, J, K, L, and M are not N, then (a) at least one of X¹, X², X³, X⁴, and X⁵ is not selected from the group consisting of hydrogen, halo, alkoxy, and hydroxy or (b) at least one of R¹, R², R³, or R⁴ is not selected from the group consisting of hydrogen, alkyl, alkenyl, haloalkyl, hydroxyalkyl, alkoxy, phenyl, substituted phenyl, halo, hydroxy, and alkoxyalkyl,
or a pharmaceutically acceptable salt, ester, or solvate thereof.

In some embodiments, the compounds of formula (I) have a structure of formula (II) or (III):

##STR00002##
wherein X⁶ and X⁷ are independently selected from the group consisting of hydrogen, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkylenylaryl, alkylenylheteroaryl, alkylenylheterocycloalkyl, alkylenylcycloalkyl, or X⁶ and X⁷ together form an optionally substituted 5 or 6 membered heterocyclic ring. In a specific class of embodiments, the compound of formula (I) is a compound selected from the group recited in Table 1, below.

A compound disclosed herein preferably exhibits an IC₅₀ in the range of about 0.1 μM to about 1000 μM, and preferably about 1 μM to about 800 μM, about 1 μM to about 500 μM, about 1 μM to about 300 μM, about 1 μM to about 200 μM, or about 1 μM to about 100 μM for inhibition of p38 MAPK.

Also disclosed herein is a composition including the compound of formula (I) and a pharmaceutically acceptable excipient.

In another aspect, disclosed herein are methods of modulating a stress activated protein kinase (SAPK) system by contacting a compound disclosed herein with a p38 mitogen-activated protein kinase (MAPK), wherein the compound exhibits an IC₅₀ in the range of about 0.1 μM to about 1000 μM for inhibition of the p38 MAPK; and wherein the contacting is conducted at a SAPK-modulating concentration that is less than an IC₃₀ for inhibition of the p38 MAPK by the compound. Contemplated p38 MAPKs include, but are not limited to, p38α, p38β, p38γ, and p38δ. In a preferred composition, the concentration of the compound disclosed herein is effective to alter TNFα release in whole blood by at least 15%.

In yet another aspect, disclosed herein are methods of modulating a SAPK system in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound as disclosed herein, wherein the compound exhibits an IC₅₀ in the range of about 0.1 μM to about 1000 μM for inhibition of p38 MAPK; and the therapeutically effective amount produces a blood or serum concentration of the compound that is less than an IC₃₀ for inhibition of p38 mitogen-activated protein kinase (MAPK). In some embodiments, the subject suffers from an inflammatory condition. The subject preferably is a mammal, more preferably human. The compound can be administered to the subject on a schedule selected from the group consisting of three times a day, twice a day, once a day, once every two days, three times a week, twice a week, and once a week.

For the compositions and methods described herein, preferred features, such as components, compositional ranges thereof, conditions, and steps, can be selected from the various examples provided herein.

DETAILED DESCRIPTION

It has now been discovered that a high therapeutic effect in treating various disorders associated with enhanced activity of kinase p38 can be achieved by using a relatively low-potency p38 kinase inhibitor compound.

Therefore, in one embodiment there is provided a method of modulating a stress-activated kinase (SAPK) system by contacting a compound as described herein with a p38 mitogen-activated protein kinase (MAPK). A preferred compound exhibits an IC₅₀ in the range of about 0.1 μM to about 1000 μM, and preferably about 1 μM to about 800 μM, about 1 μM to about 500 μM, about 1 μM to about 300 μM, about 1 μM to about 200 μM, or about 1 μM to about 100 μM for inhibition of p38 MAPK. The concentration at which the compound is contacted with p38 MAPK is preferably less than IC₃₀ for inhibition of the p38 by this compound.

Mitogen-activated protein kinases are evolutionarily conserved serine/threonine kinases involved in the regulation of many cellular events. Several MAPK groups have been identified in mammalian cells, including extracellular signal-regulated kinase (ERK), p38, and SAPK/JNK. It is believed that MAPKs are activated by their specific MAPK kinases (MAPKKs): ERK by MEK1 and MEK2, p38 by MKK3 and MKK6, and SAPK/JNK by SEK1 (also known as MKK4) and MKK7 (SEK2). These MAPKKs may also be activated by various MAPKK kinases (MAPKKKs) such as Raf, MLK, MEKK1, TAK1, and ASK1.

It is believed that the MAPK network involves at least twelve cloned highly conserved, proline-directed serine-threonine kinases which, when activated by cell stresses (e.g., oxidative stress, DNA damage, heat or osmotic shock, ultraviolet irradiation, ischemia-reperfusion), exogenous agents (e.g., anisomycin, Na arsenite, lipopolysaccharide, LPS) or pro-inflammatory cytokines, TNF-α and IL-1β, can phosphorylate and activate other kinases or nuclear proteins such as transcription factors in either the cytoplasm or the nucleus.

p38 MAPK

As used herein, “p38 MAPK” is a member (sub family) of the stress-activated protein kinase family, which includes at least 4 isoforms (α, β, γ, δ), several of which are considered important in processes critical to the inflammatory response and tissue remodeling (Lee et al. Immunopharmacol. 47:185-201 (2000)). Unless indicated otherwise, reference to “p38 MAPK,” “a p38 MAPK,” or “the p38 MAPK” contemplates any one, all, or a subset of the subfamily members. The predominant kinases in monocytes and macrophages, p38α and p38β, appear more widely expressed compared to p38γ (skeletal muscle) or p38δ (testes, pancreas, prostate, small intestine, and in salivary, pituitary and adrenal glands). A number of substrates of p38 MAP kinase have been identified including other kinases (MAPKAP K2/3, PRAK, MNK 1/2, MSK1/RLPK, RSK-B), transcription factors (ATF2/6, myocyte enhancer factor 2, nuclear transcription factor-β, CHOP/GADD153, Elk1 and SAP-1A1) and cytosolic proteins (stathmin), many of which are important physiologically.

Jiang et al. J Biol Chem 271:17920-17926 (1996) reported characterization of p38β as a 372-amino acid protein closely related to p38α. Both p38α and p38β are activated by proinflammatory cytokines and environmental stress, p38β is preferentially activated by MAP kinase kinase-6 (MKK6) and preferentially activated transcription factor 2. Kumar et al. Biochem Biophys Res Comm 235:533-538 (1997) and Stein et al. J Biol Chem 272:19509-19517 (1997) reported a second isoform of p38β, p38β2, containing 364 amino acids with 73% identity to p38α. It is believed that p38β is activated by proinflammatory cytokines and environmental stress, although the second reported p38β isoform, p38β2, appears to be preferentially expressed in the central nervous system (CNS), heart and skeletal muscle, compared to the more ubiquitous tissue expression of p38α. Furthermore, it is believed that activated transcription factor-2 (ATF-2) is a better substrate for p38β2 than for p38α.

The identification of p38γ was reported by Li. et al. Biochem Biophys Res Comm 228:334-340 (1996) and of p38δ by Wang et al. J Biol Chem 272:23668-23674 (1997) and by Kumar et al. Biochem Biophys Res Comm 235:533-538 (1997). These two p38 isoforms (γ and δ) represent a unique subset of the MAPK family based on their tissue expression patterns, substrate utilization, response to direct and indirect stimuli, and susceptibility to kinase inhibitors. It is believed that p38α and β are closely related, but diverge from γ and δ, which are more closely related to each other.

A characterization of p38 isoforms that are
was used to convert the 2 emission readouts into mP; S—S-pol filter signal, P—P-pol filter signal, and G=gain.

The mP output from the EnVision (a 384 matrix) was transferred to a plot of mP versus compound concentration. XLfit (IDBS, Guildford, England) was used to apply a 4-parameter logistic fit to the data and determine the median inhibitory concentration (IC₅₀). Preferred compounds exhibit IC₅₀ values of between about 0.05 μM and about 10 μM, preferably about 0.1 μM to about 5 μM.

Example 2

Compounds were screened for the ability to inhibit TNFα release from THP-1 cells stimulated with lipopolysaccharide (LPS) in vitro. The ability of compounds to inhibit TNFα release in this in vitro assay was correlated with the inhibition of p38 activity and TNFα expression in vivo, and was therefore an indicator of potential in vivo therapeutic activity (Lee et al. Ann. N.Y. Acad. Sci. 696:149-170 (1993); and Nature 372:739-746 (1994)).

THP-1 cells from ATCC (TIB202) were maintained at 37° C., 5% CO₂ in RPMI 1640 media (MediaTech, Herndon, Va.) containing 4.5 g/L glucose, supplemented with 10% fetal bovine serum, 1% penicillin/streptomycin and 50 μM β-mercaptoethanol.

Test compounds were initially dissolved in DMSO. Compounds were then diluted in DMSO for all subsequent dilutions. The compounds were diluted in RPMI Media immediately prior the addition to the THP-1 cells to a final concentration of 1.25% DMSO (v/v) upon addition to the cells. Compounds were tested at a final concentration on cells of 750 to 1000 μM. Where data indicates it was appropriate compounds were tested at a 5-10 fold lower concentration. The assay was performed under sterile conditions. THP-1 cells at a culture density of 6-8×10⁵ cells/mL were collected and resuspended in the RPMI media at 1×10⁶ cells/mL. 100 μl of resuspended cells were added to each well, which contained 100 μl of RPMI medium with test compound. Test compounds were prepared at 2.5 times the final concentration. Final DMSO concentration was no more than 0.5% (v/v). Cells were preincubated with compound for 60 minutes at 37° C., 5% CO₂ prior to stimulation with lipopolysaccharide (LPS) (Sigma L-2880, 1 mg/ml stock in PBS). The final LPS concentration in each well was 200 ng/ml for TNFα release. Unstimulated control cell suspensions received DMSO/RPMI Media vehicle only. Cell mixtures were incubated for 4 hours for TNFα release. 80 μl of supernatants were taken and transferred to a fresh plate and stored at −70° C. until further analysis. TNFα levels were measured using ELISA kits (R&D systems PDTA00C). A SpectraMAX M5 was used as the plate reader. The calculated amount of TNFα released was expressed as a percentage of the vehicle+LPS control.

Some compounds were tested for a TNFα dose response. Test compounds were initially dissolved in DMSO. Compounds were then serially diluted in DMSO over an appropriate range of concentrations between 2 mM and 4 μM. The compounds were diluted in RPMI Media immediately prior the addition to the THP-1 cells to a final concentration of 0.5% DMSO (v/v) upon addition to the cells. The assay was performed under sterile conditions. THP-1 cells at a culture density of 6-8×10⁵ cells/mL were collected and resuspended in the RPMI media at 1×10⁶ cells/mL. 100 μl of resuspended cells were added to each well, which contained 100 μl of RPMI media with test compound. Test compounds were prepared at 2.5 times the final concentration. Final DMSO concentration was no more than 0.5% (v/v). Cells were preincubated with compound for 60 minutes at 37° C., 5% CO₂ prior to stimulation with lipopolysaccharide (LPS) (Sigma L-2880, 1 mg/ml stock in PBS). The final LPS concentration in each well was 200 ng/ml for TNFα release. Unstimulated control cell suspensions received DMSO/RPMI Media vehicle only. Cell mixtures were incubated for 4 hours for TNFα release. 80 μl of supernatants were taken and transferred to a fresh plate and stored at −70° C. until further analysis. TNFα levels were measured using ELISA kits (R&D systems PDTA00C). A SpectraMAX M5 was used as the plate reader. Analysis was performed by non-linear regression to generate a dose response curve. The calculated IC₅₀ value was the concentration of the test compound that caused a 50% decrease in TNFα levels.

Compounds inhibit the release of TNFα in this in vitro assay. Preferred compounds exhibit IC₅₀ values for TNFα between about 1 μM and about 1000 μM, preferably about 1 μM to about 800 μM.

Example 3

Compounds were tested for cytotoxicity using an ATPlite assay (Perkin Elmer 6016731). THP-1 cells were treated with compounds as described for TNFα tests. 4 hours after LPS addition, 80 μl of media is removed for ELISA. 48 hrs after LPS addition of media and cells were mixed with 100 μl of ATPlite reagent. The mixture was shaken for 2 minutes then read for luminescence. A SpectraMAX M5 is used as the plate reader.

The calculated cytotoxicity is expressed as a percentage of the LPS/DMSO control compound. Compounds which had a low score in ATPlite compared to the LPS/DMSO control were classified as cytotoxic rather than TNFα inhibitors. Where appropriate compounds were tested at 5-10 fold lower concentrations to determine whether the compound had activity at lower, non cytotoxic concentrations.

For serial dilutions of compound, analysis is performed by non-linear regression to generate a dose response curve. The calculated CC₅₀ value is the concentration of the test compound that causes a 50% decrease in ATP levels.

Compounds may exhibit cytotoxicity which can also lower TNFα release in this in vitro assay. Preferred compounds show an ATPlite value which is 100% of the LPS/DMSO control. Preferred compounds exhibit CC₅₀ values of greater than 1 mM, preferably of undetectable toxicity.

Example 4

Compounds are screened for the ability to inhibit TNFα release from primary human peripheral blood mononuclear cells (PBMC) stimulated with lipopolysaccharide (LPS) in vitro. The ability of compounds to inhibit TNFα release in this in vitro assay is correlated with the inhibition of p38 activity and is therefore an indicator of potential in vivo therapeutic activity (Osteoarthritis & Cartilage 10:961-967 (2002); and Laufer, et al., J. Med. Chem. 45: 2733-2740 (2002)).

Human peripheral blood mononuclear cells (PBMC) are isolated by differential centrifugation through a Ficoll-HyPaque density gradient from pooled serum of 3-8 individual blood donors. Isolated PBMC contain approximately 10% CD-14 positive monocytes, 90% lymphocytes and <1% granulocytes and platelets. PBMC (106/ml) are cultured in polystyrene plates and stimulated with lipopolysaccharide (LPS; 50 ng/ml; Sigma, St. Louis, Mo.) in the presence and absence of the test compound in serial dilutions, in duplicate, for 24 hr at 37° C. in GIBCO™ RPM1 medium (Invitrogen, Carlsbad, Calif.) without serum. The TNFα level in cell supernatants is determined by ELISA using a commercially available kit (MDS Panlabs #309700).

Preferred compounds inhibit the release of TNFα in this assay with an IC₅₀ value of between about 100 μM and about 1000 μM, preferably about 200 μM to about 800 μM.

Example 5

Compounds are screened for the ability to inhibit the release of TNFα in an in vivo animal model (See, e.g., Griswold et al. Drugs Exp. Clin. Res. 19:243-248 (1993); Badger, et al. J. Pharmacol. Exp. Ther. 279:1453-1461 (1996); Dong, et al. Annu. Rev. Immunol. 20:55-72 (2002) (and references cited therein); Ono, et al., Cellular Signalling 12:1-13 (2000) (and references cited therein); and Griffiths, et al. Curr. Rheumatol. Rep. 1:139-148 (1999)).

Without being bound by any particular theory, it is believed that inhibition of TNFα in this model is due to inhibition of p38 MAP kinase by the compound.

Male Sprague-Dawley rats (0.2-0.35 kg) are randomly divided into groups of six or more and are dosed intravenously by infusion or bolus injection, or are dosed orally with test compounds in a suitable formulation in each case. At ten minutes to 24 hr following treatment lipopolysaccharide E. coli/0127:B8 (0.8 mg/kg) is administered IV in the presence of D-galactosamine. Blood levels are samples are collected 1.5 hours post-treatment with LPS. Serum TNFα and/or IL-6 determined using an appropriate ELISA kit and compared to that from vehicle-treated control.

Preferred compounds inhibit the release of TNFα in this in vivo assay. Preferred compounds exhibit an ED₅₀ value of less than 500 mg/kg, preferably less than 400 mg/kg, preferably less than 200 mg/kg, preferably less than 100 mg/kg, more preferably, less than 50 mg/kg, more preferably, less than 40 mg/kg, more preferably, less than 30 mg/kg, more preferably, less than 20 mg/kg, more preferably, less than 10 mg/kg.

The methods of determining the IC₅₀ of the inhibition of p38 by a compound include any methods known in the art that allow the quantitative detection of any of the downstream substrates of p38 MAPK as described above. Therefore, these methods additionally include but limited to detection of expression of genes known to be regulated by p38 either individually, or by gene arrays.

Results of Biological Tests

The data sets for each compound assayed as described in Examples 2 (TNFα inhibition) and 3 (ATPlite assay), above were binned based on percentage of control (POC) data. For a subset of compounds with data from dose response curves, calculated POC values at the 750 μM screening concentration were derived from the existing EC₅₀, CC₅₀ and Hill Slope values using the standard four-paramater four-parameter curve fit equation assuming an upper asymptope asymptote of 100% and a lower asymptope asymptote of 0%. The relevant equations are: POC_TNFα=(100−0)/(1+(750/EC₅₀)^Hill Slope) and POC_ATPlite=(100−0)/(1+(750/CC₅₀)^Hill Slope). These values were averaged with existing POC determinations create a data set that could be appropriately binned.

Data were binned using the following criteria: Bin A (greatest inhibition) POC<33; Bin B POC 33 and <66; Bin C 66-100, with either ATPlite POC>90 or an ATPlite POC at least two-fold above the TNFα POC. When ATPlite POC for a given compound was not either 1) greater than 90, or 2) at least two-fold above the TNFα POC the compound was placed in bin C regardless of the TNFα POC. Adjustments were made to the binning of compounds 10, 21, 47, 160, 179, 189, 193, based on full dose response curves with CC₅₀:EC₅₀ ratios that were either >2 or <2, respectively. In the former case, the compounds were left in the appropriate bin based on TNFα POC and in the latter case they were placed in bin C.

TABLE 2

Example Bin

1       A
2       C
3       C
4       C
5       C
6       A
7       C
8       B
9       C
10      C
11      C
12      C
13      C
14      C
15      C
16      C
17      C
18      B
19      A
20      C
21      C
22      A
23      C
24      C
25      C
26      C
27      C
28      C
29      A
30      C
31      C
32      C
33      C
34      C
35      C
36      C
37      C
38      C
39      C
40      C
41      A
42      C
43      C
44      C
45      C
46      C
47      A
48      C
49      C
50      B
51      C
52      C
53      C
54      C
56      C
58      C
59      C
60      A
61      C
62      C
63      C
64      C
65      C
66      C
67      C
68      C
69      C
70      C
72      A
73      A
74      A
75      C
77      C
78      C
79      C
80      A
81      C
82      A
83      C
84      A
85      C
86      C
87      C
88      C
89      A
90      B
91      C
92      C
93      A
94      A
96      A
97      A
98      C
99      C
100     C
101     C
102     A
103     C
104     C
105     A
106     A
107     C
108     C
109     A
110     C
111     C
112     C
113     C
114     B
115     C
116     C
117     A
118     A
119     C
120     B
121     A
122     C
123     C
124     C
125     C
126     C
127     B
128     A
129     B
130     A
131     C
132     A
133     C
134     C
135     A
136     A
137     A
138     A
139     A
140     B
141     A
142     C
143     C
144     C
145     A
147     A
148     C
149     C
150     C
151     C
152     A
153     A
154     C
155     A
156     C
158     C
159     A
160     C
161     C
162     C
163     B
164     C
166     C
167     B
168     B
169     A
171     C
172     A
173     C
174     C
177     A
178     A
179     C
182     C
183     A
184     C
185     C
186     C
187     C
188     C
189     B
190     C
192     C
193     B
195     C
197     C
200     A
201     C
202     C
203     A
209     C
210     C
211     A
212     C
213     C
214     A
215     C
216     B
217     A
218     C
219     C
220     C
221     C
222     C
223     C
224     C
225     B
226     C
227     C
228     A
229     C
230     C
231     C
232     B
233     C
234     C
235     A
236     A
237     C
238     B
239     C
240     B
241     A
242     A
243     C
244     C
245     A
246     C
247     C
248     C
249     A
250     B
251     C
252     A
253     C
254     A
255     C
256     C
257     A
258     A
259     C
260     B
261     C
262     B
263     C
264     C
265     C
266     C
267     A
268     A
269     C
270     C
271     C
272     A
273     A
274     A
275     C
276     C
277     A
278     A
279     A
280     C
281     C
282     B
283     A
284     C
285     A
286     C
287     B
288     A
289     C
290     A
291     A
292     C
293     C
294     A
295     A
296     C
297     C

While the present invention has been described in some detail for purposes of clarity and understanding, one skilled in the art will appreciate that various changes in form and detail can be made without departing from the true scope of the invention. All figures, tables, appendices, patents, patent applications and publications, referred to above, are incorporated herein by reference.

Claims

1. A compound of formula II (II)

2. The compound of claim 1, wherein one of X¹, X², and X³ is not hydrogen.

3. A compound having a structure of formula (III) or formula (IV)

4. The compound of claim 3, wherein X⁷ is hydrogen.

5. The compound of claim 1, wherein R¹ is selected from the group consisting of hydrogen, 4-pyridyl, cyclopropanyl, 2-furanyl, cyano, H₂NSO₂, (CH₃)₂NSO₂, fluoro, 4-(3,5-dimethyl)-isoxazolyl, 4-pyrazolyl, 4-(1-methyl)-pyrazolyl, 5-pyrimidinyl, 2-imidazolyl, and thiazolyl.

6. The compound of claim 1, wherein at least one of X¹, X², or X³ is alkyl or cycloalkyl.

7. The compound of claim 1, wherein at least one of X¹, X², or X³ is haloalkyl.

8. The compound of claim 1, wherein at least one of X¹, X², or X³ is alkenyl.

9. The compound of claim 1, wherein at least one of X¹, X², or X³ is amino.

10. The compound of claim 1 having a structure selected from the group consisting of:

11. The compound of claim 1, wherein the compound exhibits an IC₅₀ in a range of about 100 μM to about 1000 μM for inhibition of p38 MAPK.

12. The compound of claim 11, wherein the compound exhibits an IC₅₀ is in the range of about 200 μM to about 800 μM.

13. The compound of claim 1, wherein the compound exhibits an EC₅₀ in the range of about 0.1 μM to about 1000 μM for inhibition of TNFα secretion in a bodily fluid in vivo.

14. A composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.

15. The compound of claim 2, wherein R² is selected from the group consisting of substituted or unsubstituted aryl; unsubstituted heteroaryl; heteroaryl substituted with one or more substituents selected from halo, unsubstituted alkyl, alkenyl, OCF₃, NO₂, CN, NC, OH, alkoxy, haloalkoxy, amino, CO₂H, and CO₂alkyl; haloalkylcarbonyl; cycloalkyl; hydroxylalkyl; sulfonamido; and unsubstituted cycloheteroalkyl; or R² and R¹ together form an optionally substituted 5-membered nitrogen-containing heterocyclic ring.

16. The compound of claim 15, selected from the group consisting of:

17. A compound selected from the group consisting of:

18. The compound of claim 3 having a structure selected from the group consisting of:

19. A compound selected from the group consisting of: