3) Structure–activity relationships for the synthesis of selective cyclooxygenase 2 inhibitors an overview (2009–2016).pdf (original) (raw)
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Proceedings of the National Academy of Sciences, 2000
All nonsteroidal antiinflammatory drugs (NSAIDs) inhibit the cyclooxygenase (COX) isozymes to different extents, which accounts for their anti-inflammatory and analgesic activities and their gastrointestinal side effects. We have exploited biochemical differences between the two COX enzymes to identify a strategy for converting carboxylate-containing NSAIDs into selective COX-2 inhibitors. Derivatization of the carboxylate moiety in moderately selective COX-1 inhibitors, such as 5,8,11,14-eicosatetraynoic acid (ETYA) and arylacetic and fenamic acid NSAIDs, exemplified by indomethacin and meclofenamic acid, respectively, generated potent and selective COX-2 inhibitors. In the indomethacin series, esters and primary and secondary amides are superior to tertiary amides as selective inhibitors. Only the amide derivatives of ETYA and meclofenamic acid inhibit COX-2; the esters are either inactive or nonselective. Inhibition kinetics reveal that indomethacin amides behave as slow, tight-binding inhibitors of COX-2 and that selectivity is a function of the time-dependent step. Site-directed mutagenesis of murine COX-2 indicates that the molecular basis for selectivity differs from the parent NSAIDs and from diarylheterocycles. Selectivity arises from novel interactions at the opening and at the apex of the substrate-binding site. Lead compounds in the present study are potent inhibitors of COX-2 activity in cultured inflammatory cells. Furthermore, indomethacin amides are orally active, nonulcerogenic, anti-inflammatory agents in an in vivo model of acute inflammation. Expansion of this approach can be envisioned for the modification of all carboxylic acid-containing NSAIDs into selective COX-2 inhibitors. This paper was submitted directly (Track II) to the PNAS office.
Evaluation of COX-1/COX-2 selectivity and potency of a new class of COX-2 inhibitors
European Journal of Pharmacology, 2008
A new class of selective cyclooxygenase-2 (COX-2) inhibitors has been identified by high throughput screening. Structurally distinct from previously described selective COX-2 inhibitors, these benzopyrans contain a carboxylic acid function and CF 3 functionality. The compound SC-75416 is a representative of this class. A range if in vitro and in vivo tests were employed to characterize its potency and selectivity. Using human recombinant enzymes, this compound displays a concentration that provides 50% inhibition (IC 50 ) of 0.25 μM for COX-2 and 49.6 μM for COX-1. A mutation of the side pocket residues in COX-2 to COX-1 had little effect on potency suggesting that these inhibitors bind in a unique manner in COX-2 distinct from COX-2 inhibiting diaryl heterocycles. Using rheumatoid arthritic synovial cells stimulated with interleukin-1β (IL-1β) and washed platelets the compound displayed IC 50 of 3 nM and 400 nM respectively. Potency and selectivity was maintained but predictably right shifted in whole blood with IC 50 of 1.4 μM for lipopolysaccharide (LPS) stimulated induction of COX-2 and N 200 μM for inhibition of platelet thromboxane production. SC-75416 is 89% bioavailable and its in vivo half life is sufficient for once a day dosing. In the rat air pouch model of inflammation, the compound inhibited PGE 2 production with an effective dose that provides 50% inhibition (ED 50 ) of 0.4 mg/kg, while sparing gastric prostaglandin E2 (PGE 2 ) production with an ED 50 of 26.5 mg/kg. In a model of acute inflammation and pain caused by carrageenan injection into the rat paw, the compound reduced edema and hyperalgesia with ED 50 s of 2.7 and 4 mg/kg respectively. In a chronic model of arthritis the compound demonstrated an ED 50 of 0.081 mg/kg and an ED 80 of 0.38 mg/kg. In a model of neuropathic pain, SC-75416 had good efficacy. This compound's unique chemical structure and effect on COX enzyme binding and activity as well as its potency and selectivity may prove useful in treating pain and inflammation.
The Journal of Immunology, 2001
T he prostanoids prostacyclin (PGI 2 ) 3 and thromboxane A 2 (TXA 2 ) play an essential role in the maintenance of vascular homeostasis. PGI 2 is a vasodilator and an inhibitor of platelet aggregation, whereas TXA 2 is a vasoconstrictor and a promoter of platelet aggregation (1). As a consequence of their opposing roles, an imbalance in PGI 2 or TXA 2 production has been implicated in the pathophysiology of many thrombotic and cardiovascular disorders (1-3). Therefore, it is important to understand factors and conditions that might affect the balance of PGI 2 / TXA 2 synthesis. PGI 2 and TXA 2 are products of arachidonic acid (AA) metabolism by cyclooxygenase (COX), followed by metabolism of the COX product, PGH 2 , by the terminal synthase enzymes, prostacyclin or TX synthase, respectively. Two isoforms of COX have been identified: COX-1 is expressed constitutively in most cell types, whereas COX-2 is induced by inflammatory stimuli such as bacterial endotoxin and cytokines. Also, several different prostanoid terminal synthases can be present within the one cell, and it is not known what determines the relative rate of production of each individual prostanoid within the same cell. In monocytic cells, it has been observed that the ratio of PGE 2 /TXA 2 produced is not fixed, but varies according to which COX isoform is present. For example, in rat peritoneal macrophages, under conditions in which only COX-1 was expressed, TXA 2 was synthesized in excess of PGE 2 . However, under conditions of stimulation in which COX-2 was induced, the profile of prostanoid production shifted to favor PGE 2 over TXA 2 production (4, 5).
Pharmaceuticals, 2018
Prostaglandins and thromboxane are lipid signaling molecules deriving from arachidonic acid by the action of the cyclooxygenase isoenzymes COX-1 and COX-2. The role of cyclooxygenases (particularly COX-2) and prostaglandins (particularly PGE2) in cancer-related inflammation has been extensively investigated. In contrast, COX-1 has received less attention, although its expression increases in several human cancers and a pathogenetic role emerges from experimental models. COX-1 and COX-2 isoforms seem to operate in a coordinate manner in cancer pathophysiology, especially in the tumorigenesis process. However, in some cases, exemplified by the serous ovarian carcinoma, COX-1 plays a pivotal role, suggesting that other histopathological and molecular subtypes of cancer disease could share this feature. Importantly, the analysis of functional implications of COX-1-signaling, as well as of pharmacological action of COX-1-selective inhibitors, should not be restricted to the COX pathway a...