Design, synthesis, and biological evaluation of ketoprofen analogs as potent cyclooxygenase-2 inhibitors

被引：65

作者：

Zarghi, Afshin ^{[1
]}

Ghodsi, Razieh ^{[1
]}

机构：

[1] Shaheed Beheshti Univ Med Sci, Sch Pharm, Dept Pharmaceut Chem, Tehran, Iran

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2010年 / 18卷 / 16期

关键词：

Cyclooxygenase-2; inhibition; Ketoprofen analogs; Quinoline-4-carboxylic acid; Molecular modeling; SELECTIVE COX-2 INHIBITORS; DERIVATIVES; INDOMETHACIN; ESTERS; SITE;

D O I：

10.1016/j.bmc.2010.06.094

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

A new series of ketoprofen analogs were synthesized to evaluate their biological activities as selective cyclooxygenase-2 (COX-2) inhibitors. In vitro COX-1 and COX-2 inhibition studies showed that all compounds were potent and selective inhibitors of the COX-2 isozyme with IC(50) values in the highly potent 0.057-0.085 mu M range, and COX-2 selectivity indexes in the 115 to >1298.7 range. Compounds possessing azido pharmacophore group (8a and 8b) exhibited highly COX-2 inhibitory selectivity and potency even more than reference drug celecoxib. Molecular modeling studies indicated that the azido substituent can be inserted deeply into the secondary pocket of COX-2 active site for interactions with Arg(513). (C) 2010 Elsevier Ltd. All rights reserved.

引用

页码：5855 / 5860

页数：6

共 22 条

[1] Structure-based design of COX-2 selectivity into flurbiprofen [J].

Bayly, CI ;

Black, WC ;

Léger, S ;

Ouimet, N ;

Ouellet, M ;

Percival, MD .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 1999, 9 (03) :307-312

[2] 1,5-diarylpyrrole-3-acetic acids and esters as novel classes of potent and highly selective cyclooxygenase-2 inhibitors [J].

Biava, M ;

Porretta, GC ;

Cappelli, A ;

Vomero, S ;

Manetti, F ;

Botta, M ;

Sautebin, L ;

Rossi, A ;

Makovec, F ;

Anzini, M .

JOURNAL OF MEDICINAL CHEMISTRY, 2005, 48 (09) :3428-3432

[3]

DeWitt DL, 1999, MOL PHARMACOL, V55, P625

[4] Design and synthesis of celecoxib and rofecoxib analogues as selective cyclooxygenase-2 (COX-2) inhibitors: Replacement of sulfonamide and methylsulfonyl pharmacophores by an azido bioisostere [J].

Habeeb, AG ;

Rao, PNP ;

Knaus, EE .

JOURNAL OF MEDICINAL CHEMISTRY, 2001, 44 (18) :3039-3042

[5] Prostaglandin synthase 2 [J].

Herschman, HR .

BIOCHIMICA ET BIOPHYSICA ACTA-LIPIDS AND LIPID METABOLISM, 1996, 1299 (01) :125-140

[6] Patent in vitro methicillin-resistant Staphylococcus aureus activity of 2-(1H-indol-3-yl)quinoline derivatives [J].

Hoemann, MZ ;

Kumaravel, G ;

Xie, RL ;

Rossi, RF ;

Meyer, S ;

Sidhu, A ;

Cuny, GD ;

Hauske, JR .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2000, 10 (23) :2675-2678

[7] Increased cyclooxygenase 2 (COX-2) expression occurs frequently in precursor lesions of human adenocarcinoma of the lung [J].

Hosomi, Y ;

Yokose, T ;

Hirose, Y ;

Nakajima, R ;

Nagai, K ;

Nishiwaki, Y ;

Ochiai, A .

LUNG CANCER, 2000, 30 (02) :73-81

[8] Indolyl esters and amides related to indomethacin are selective COX-2 inhibitors [J].

Kalgutkar, AS ;

Crews, BC ;

Saleh, S ;

Prudhomme, D ;

Marnett, LJ .

BIOORGANIC & MEDICINAL CHEMISTRY, 2005, 13 (24) :6810-6822

[9] Amide derivatives of meclofenamic acid as selective cyclooxygenase-2 inhibitors [J].

Kalgutkar, AS ;

Rowlinson, SW ;

Crews, BC ;

Marnett, LJ .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2002, 12 (04) :521-524

[10] ASPIRIN-INDUCED GASTRIC-MUCOSAL INJURY - LESSONS LEARNED FROM ANIMAL-MODELS [J].

KAUFFMAN, G .

GASTROENTEROLOGY, 1989, 96 (02) :606-614

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