Design and synthesis of sulfonyl-substituted 4,5-diarylthiazoles as selective cyclooxygenase-2 inhibitors

Carter, Jeffery S.; Rogier, D. Joseph; Graneto, Matthew J.; Seibert, Karen; Koboldt, Carol M.; Zhang, Yan; Talley, John J.

doi:10.1016/s0960-894x(99)00158-4

Cited by 34 publications

(16 citation statements)

References 12 publications

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“…Examples of central heterocycles include 5-or 6-membered rings that contain one (thiophenes [35][36][37], pyrroles [59][60][61], furans [62,63] and pyridines Pyrroles Eurans 2(5H)-Furanones Thiazo1es 21 [64][65][66]), two (thiazoles [67,68], oxazoles and the corresponding oxazolones [69,70], imidazoles [71][72][73], isoxazoles [74][75][76], pyrazoles [38,[77][78][79]), or three (thiadiazole [80]) heteroatoms (Fig. 6).…”

Section: H Ete Rocyclesmentioning

confidence: 99%

Structural diversity of selective COX-2 inhibitors

Marnett

Kalgutkar

2004

COX-2 Inhibitors

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Section: H Ete Rocyclesmentioning

confidence: 99%

Structural diversity of selective COX-2 inhibitors

Marnett

Kalgutkar

2004

COX-2 Inhibitors

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“…These data are consistent with the observations that the relative activity profiles are 11f (R 1 = F, R 2 = MeS) > 11g (R 1 = MeS, R 2 = F) and 11p (R 1 = MeSO 2 , R 2 = F) > 11o (R 1 = F, R 2 = MeSO 2 ). It is well documented that para-phenyl substituents in isomeric compounds can dramatically alter COX-2 selectivity and potency [Khanna et al, 1997b;Carter et al, 1999]. Compounds having R 1 or R 2 = F, MeSO 2 and MeS as paraphenyl substituents exhibited the most potent AI activity, where the AI potency order for the C-4 phenyl para-R 1 -substituents was F (11b) > MeSO 2 (11n) > MeS (11e) > MeSO (11j) > H (11h), and for the C-5 phenyl para-R 2 -substituents was MeS (11d) > F (11a) > MeSO 2 (11m) > MeSO (11i) > H (11h).…”

Section: Analgesic and Antiinflammatory Structureactivity Relationshimentioning

confidence: 99%

“…The identification of the tricyclic DuP 697 (1) [Gans et al, 1990], a selective COX-2 inhibitor, stimulated other studies involving replacement of the thiophene ring of 1 by various five-membered heterocyclic rings, including pyrrole (2) [Wilkerson et al, 1995], imidazole (3) [Khanna et al, 1997a], thiazole (4) [Carter et al, 1999], 2-(5H)-furanone (5) [Prasit et al, 1999], pyrazole (6-7) [Penning et al, 1997], and oxazole (8) [Silvestre et al, 1998] (see structures in Fig. 1).…”

Section: Introductionmentioning

confidence: 99%

“…The S-atom of the MeSO 2 substituent, also located inside the secondary pocket, is about 5.6 Å from the entrance of the secondary pocket (Val 523 ), as shown in Figure 7. A small lipophilic central ring substituent (Me, CF 3 ) frequently enhances, or is often a requirement for, COX-2 selectivity [Carter et al, 1999;Penning et al, 1997]. It was anticipated that incorporation of a C-5 CF 3 substituent on a 3,4-diarylisoxazole compound (15 or 21) would reorient the isoxazole ring such that the isoxazole ring is positioned similar to the pyrazole ring of SC-588, and the MeSO 2 moiety on the aryl ring is positioned to facilitate its entry into the COX-2 secondary pocket (Val 523 ).…”

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confidence: 99%

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Design and syntheses of diarylisoxazoles: Novel inhibitors of cyclooxygenase‐2 (COX‐2) with analgesic‐antiinflammatory activity

Habeeb

Rao

Knaus

2000

Drug Development Research

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A group of 4,5-diphenylisoxazoles (11ap), 3,4-diphenyl-5-trifluoromethylisoxazoles (15, 21), and 4,5-diphenyl-3-methylsulfonamidoisoxazole (23) possessing a variety of substituents (H, F, MeS, MeSO, MeSO 2 ) at the para-position of one of the phenyl rings were synthesized for evaluation as analgesic, and selective COX-2 inhibitory antiinflammatory (AI), agents. Although the 4,5-diphenylisoxazole group of compounds (11ap) exhibited potent analgesic and AI activities, those compounds evaluated (11a, 11b, 11m) were more selective inhibitors of COX-1 than COX-2, with the exception of 4-(4-methylsulphonylphenyl)-5-phenylisoxazole (11n) that showed a modest COX-2 selectivity index (SI) of 2.1. In contrast, 3-(4-methylsulphonylphenyl)-4-phenyl-5-trifluoromethylisoxazole (15), which retained good analgesic and AI activities, was a highly potent and selective COX-2 inhibitor (COX-1 IC 50 > 500 µM; COX-2 IC 50 < 0.001 µM) with a COX-2 SI of > 500,000, relative to the reference drug celecoxib (COX-1 IC 50 = 22.9 µM; COX-2 IC 50 = 0.0567 µM) with a COX-2 SI of 404. The 3-phenyl-4-(4-methylsulphonylphenyl) regioisomer (21) was a less potent inhibitor (COX-1 IC 50 = 252 µM; COX-2 IC 50 = 0.2236 µM) with a COX-2 SI of 1122, relative to the regioisomer (15). The related compound 4,5-diphenyl-3-methylsulfonamidoisoxazole (23) exhibited similar (to 21) potency and COX-2 selectivity (COX-1 IC 50 > 200 µM; COX-2 IC 50 = 0.226 µM) with an SI of 752. A molecular modeling (docking) study for the most potent, and selective, COX-2 inhibitor (15) in the active site of the human COX-2 enzyme showed the C-5 CF 3 substituent is positioned 3.37 Å from the phenolic OH of Tyr 355 , and 6.91 Å from the Ser 530 OH. The S-atom of the MeSO 2 substituent is positioned deep (7.40 Å from the entrance) inside the COX-2 secondary pocket (Val 523 ). These studies indicate a C-5 CF 3 (15, 21), or C-3 NHSO 2 Me (23), central isoxazole ring substituent is crucial to selective inhibition of COX-2 for this class of compounds. Drug Dev. Res. 51:273-286, 2000.

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“…The classical method for the synthesis of thiazoles is the Hantzsch process, in which an a-haloketone is condensed with a thioamide [5]. This method gives excellent yields for simple thiazoles; however, for some substituted examples, low yields have been reported as a result of dehalogenation of the a-haloketone during the reaction [4] [6]. As part of our current studies on the development of new routes in heterocycle synthesis [7 -10], we report an efficient synthetic route to functionalized thiazoles.…”

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confidence: 99%