Search

In this manuscript, we report the discovery of the substituted 2-trifluoromethyl-2H-benzopyran-3-carboxylic acids as a novel series of potent and selective cyclooxygenase-2 (COX-2) inhibitors. We provide the structure–activity relationships, optimization of design, testing criteria, and human half-life data. The challenge of a surprisingly long half-life (t1/2 = 360 h) of the first clinical candidate 1 and human t1/2 had been difficult to predict based on allometric scaling for this class of highly ppb compounds. We used a microdose strategy which led to the discovery of clinical agents 18c-(S), 29b-(S), and 34b-(S) with human half-life of 57, 13, and 11 h.

5-Lipoxygenase (LOX) is an important arachidonic acid-metabolizing enzyme producing leukotrienes and other proinflammatory lipid mediators with potent pathophysiological functions in asthma and other inflammatory diseases. 4-(3-(4-(1-Methyl-1H-pyrazol-5-yl)phenylthio)phenyl)-tetrahydro-2H-pyran-4-carboxamide (PF-4191834) is a novel, selective non-redox 5-lipoxygenase inhibitor effective in inflammation and pain. In vitro and in vivo assays were developed for the evaluation of a novel 5-LOX inhibitor using conditions of maximal enzyme activity. PF-4191834 exhibits good potency in enzyme- and cell-based assays, as well as in a rat model of acute inflammation. Enzyme assay results indicate that PF-4191834 is a potent 5-LOX inhibitor, with an IC(50) = 229 +/- 20 nM. Furthermore, it demonstrated approximately 300-fold selectivity for 5-LOX over 12-LOX and 15-LOX and shows no activity toward the cyclooxygenase enzymes. In addition, PF-4191834 inhibits 5-LOX in human blood cells, with an IC(80) = 370 +/- 20 nM. This inhibitory concentration correlates well with plasma exposures needed for in vivo efficacy in inflammation in models of inflammatory pain. The combination of potency in cells and in vivo, together with a sustained in vivo effect, provides PF-4191834 with an overall pharmacodynamic improvement consistent with once a day dosing.

A series of sulfonamide-substituted 4,5-diarylthiazoles was prepared via three synthetic routes as selective COX-2 inhibitors. Recently in the synthesis of selective COX-2 inhibitors we have discovered that the sulfonamide moiety is a suitable replacement for the methylsulfonyl moiety yielding compounds with activity both in vitro and in vivo.

A series of sulfonamide-substituted 4,5-diarylthiazoles was prepared via three synthetic routes as selective COX-2 inhibitors. Recently in the synthesis of selective COX-2 inhibitors we have discovered that the sulfonamide moiety is a suitable replacement for the methylsulfonyl moiety yielding compounds with activity both in vitro and in vivo.

A series of novel sulfone substituted 4,5-diarylthiazoles have been synthesized and evaluated for their inhibition of the two isoforms of human cyclooxygenase (COX-1 and COX-2). This series displays exceptionally selective COX-2 inhibition.

Zileuton, a redox and iron chelator 5-lipoxygenase (5-LOX) inhibitor and, leukotriene receptor antagonists are presently used clinically in the long term treatment of asthma. Recent data implicate 5-LOX pathway in pain signaling. We report 5-LOX expression in the central nervous system (CNS) and analyze the pain efficacy of a new class of non redox, non iron chelating 5-LOX inhibitor. CJ-13610, 4-(3-(4-(2-methyl-1H-imidazol-1-yl) phenylthio) phenyl)-tetrahydro-2H-pyran-4-carboxamide, demonstrated antihyperalgesic activity in inflammatory pain models including the acute carrageenan model and the chronic inflammatory model using complete Freund's adjuvant. Following complete Freund's adjuvant stimulus leukotrieneB(4) concentration in the brain was elevated (9+/-1 ng/g, mean+/-S.E.M.) by about 3 times that of the control group (3+/-0.11, mean+/-S.E.M.). Hyperalgesia and leukotrieneB(4) concentration were both reversed following CJ-13610 treatment. Furthermore, we demonstrate CJ-13610 efficacy against osteoarthritis like pain using the rat medial meniscal transection model. CJ-13610 at oral doses of 0.6, 2 and 6 mg/kg/day reversed two modalities of pain in this model; tactile allodynia and weight bearing differential. Taken together, these data suggest that 5-LOX pathway and the leukotriene products are important mediators of pain.

A series of pyrazole inhibitors of p38 mitogen-activated protein (MAP) kinase were designed using a binding model based on the crystal structure of 1 (SC-102) bound to p38 enzyme. New chemistry using dithietanes was developed to assemble nitrogen-linked substituents at the 5-position of pyrazoles. Calculated log D was used in tandem with structure-based design to guide medicinal chemistry strategy and improve the in vivo activity of a series of molecules. The crystal structure of an optimized inhibitor, 4 (SC-806), in complex with p38 enzyme was obtained to confirm the hypothesis that the addition of a basic nitrogen to the molecule induces an interaction with Asp112 of p38 alpha. A compound identified from this series was efficacious in an animal model of rheumatic disease.

In this article, we describe the radiosynthesis and evaluation of 18F-labeled cyclooxygenase (COX) inhibitors. 18F-SC63217 is selective to COX-1 and has a COX-1 inhibitory concentration of 50% (IC(50))10 nmol/L and a COX-2 IC(50)100 micromol/L. 18F-SC58125 has IC(50) values of100 micromol/L (COX-1) and86 nmol/L (COX-2).SC63217 and SC58125 were both labeled with 18F by nucleophilic displacement of a trimethylammonium triflate salt using a dedicated microwave cavity. Each compound was evaluated in vitro using a murine macrophage cell line (J774). COX-2 was stimulated in these cells by treatment with lipopolysaccharide and interferon-gamma. Both radiotracers were further investigated in vivo using rat biodistribution techniques. Brain uptake of the COX-2 inhibitor, 18F-SC58125, was further investigated by brain PET of a baboon.The in vitro studies showed that uptake of 18F-SC58125 was increased in stimulated cells and was totally inhibited by the addition of nonradioactive SC58125. In contrast, no increase in uptake was seen for 18F-SC63217. In the biodistribution experiments, 18F-SC63217 showed much higher uptake in the small intestine (an organ known to express high levels of COX-1) than did 18F-SC58125. Higher levels of 18F-SC58125 were observed in the kidney, an organ known to contain high levels of COX-2 rather than COX-1. 18F-SC58125 was retained in brain tissue. PET images of the baboon showed no regional distribution of the radiotracer in the brain.We have developed a radiosynthetic route that can yield 18F-labeled selective inhibitors of COX-1 or COX-2. Both compounds have been fully characterized in vitro and in vivo. Our results indicate that 18F-SC58125 has potential as a marker of COX-2 activity but that, because of high nonspecific binding, 18F-SC63217 was not a good choice as a marker of COX-1.

A series of novel sulfone substituted 4,5-diarylthiazoles have been synthesized and evaluated for their inhibition of the two isoforms of human cyclooxygenase (COX-1 and COX-2). This series displays exceptionally selective COX-2 inhibition.

A series of sulfonamide-containing 1,5-diarylpyrazole derivatives were prepared and evaluated for their ability to block cyclooxygenase-2 (COX-2) in vitro and in vivo. Extensive structure-activity relationship (SAR) work was carried out within this series, and a number of potent and selective inhibitors of COX-2 were identified. Since an early structural lead (1f, SC-236) exhibited an unacceptably long plasma half-life, a number of pyrazole analogs containing potential metabolic sites were evaluated further in vivo in an effort to identify compounds with acceptable pharmacokinetic profiles. This work led to the identification of 1i (4-[5-(4-methylphenyl)-3-(trifluoromethyl)- H-pyrazol-1-yl]benzenesulfonamide, SC-58635, celecoxib), which is currently in phase III clinical trials for the treatment of rheumatoid arthritis and osteoarthritis.