Identification of Novel Cyclooxygenase-2 Selective Inhibitors Using Pharmacophore Models

Abstract

In the present study we have investigated whether pharmacophore models may account for the activity and selectivity of the known cyclooxygenase-2 (COX-2) selective inhibitors of the phenylsulfonyl tricyclic series, i.e., Celecoxib (1) and Rofecoxib (3), and whether transferring this structural information onto the frame of a nonsteroidal antiinflammatory drug (NSAID), known to tightly bind the enzyme active site, may be useful for designing novel COX-2 selective inhibitors. With this aim we have developed a pharmacophore based on the geometric disposition of chemical features in the most favorable conformation of the COX-2 selective inhibitors SC-558 (2; analogue of Celecoxib (1)) and Rofecoxib (3) and the more restrained compounds 4 (DFU) and 5. The pharmacophore model contains a sulfonyl S atom, an aromatic ring (ring plane A) with a fixed position of the normal to the plane, and an additional aromatic ring (ring plane B), both rings forming a dihedral angle of 290 degrees +/- 10 degrees. The final disposition of the pharmacophoric groups parallels the geometry of the ligand SC-558 (2) in the known crystal structure of the COX-2 complex. Moreover, the nonconserved residue 523 is known to be important for COX-2 selective inhibition; thus, the crystallographic information was used to position an excluded volume in the pharmacophore, accounting for the space limits imposed by this nonconserved residue. The geometry of the final five-feature pharmacophore was found to be consistent with the crystal structure of the nonselective NSAID indomethacin (6) in the COX-2 complex. This result was used to design indomethacin analogues 8 and 9 that exhibited consistent structure-activity relationships leading to the potent and selective COX-2 inhibitor 8a. Compound 8a (LM-1685) was selected as a promising candidate for further pharmacological evaluation.

Pharmacophore-based virtual screening versus docking-based virtual screening: a benchmark comparison against eight targets

“…Thus, the common features of all the generated hypotheses were summarized and used as the query features in the virtual screening. In addition, the excluded volumes were involved in the pharmacophore models to improve effectiveness of virtual screening [42][43][44] . All the pharmacophore models were exported and translated by a script into Catalyst pharmacophore files for further virtual screening.…”

Synthesis of Some Novel Oxadiazole and Oxadiazoline Analogues for Their Antiinflammatory Activity

“…2-( 4-Substituted-phenyl ) -5-( naphthalen-1-yloxymethyl)- [1,3,4]oxadiazole (5a f): A mixture of 4a f (0.01 mol), anhydrous sodium acetate (0.02 mol), and glacial acetic acid was placed in a round-bottomed ‰ask equipped with a separating funnel for the addition of bromine. Bromine (0.8 ml in 5 ml of glacial acetic acid) was added slowly to it while stirring magnetically.…”

“…1,3,4-Oxadiazoles have antiin‰ammatory properties by virtue of a dual mechanism, i.e., inhibiting both COX and LOs to reduce gastric ulcer formation. 1,2) Numerous studies have been performed with the aim of exploring the antiin‰ammatory properties of 1,3,4-oxadiazole analogues. 3 7) Those studies found that 1,3,4-oxadiazole analogues are equipotent with phenylbutazone, naproxen and other NSAIDs.…”

Novel Fused 1h- Imidazo[1,2-B] Pyrazole Analogues as Anti-Inflammatory and Analgesic Agents With Their Molecular Docking Studies Against Cox-1 and Cox-2

“…Although both isoforms catalyze the same biochemical transformation, they are subject to a different expression regulation. COX-1 is a constitutive enzyme and is responsible for the physiological function of prostaglandins (PGs) like maintenance of the integrity of the gastric mucosa and provides adequate vascular homeostasis, whereas COX-2 is an inducible enzyme and is expressed only after an inflammatory stimulus [1]. In recent years, many heterocyclic moieties have been designed and synthesised as potent antiinflammatory drugs.…”