QSAR and conformational analysis of the antiinflammatory agent amfenac and analogues

Abstract

The new nonsteroidal antiinflammatory drug (NSAID) arylacetic amfenac (2-amino-3-benzoylphenylacetic acid) and 19 substituted derivatives were studied in order to correlate the biological activities with the structure-related parameters. The geometry of amfenac in neutral and anionic form was totally optimized, starting from standard geometries and crystallographic data, using semiempirical AM1 and MNDO quantum-mechanical methods. Conformational analysis shows the existence of a rigid structure for rotations of the acetic acid chain (alpha degrees) and the central carbonyl group (gamma degrees) around the bonds with the phenylamine ring, whereas the carboxyl group (beta degrees) and the phenyl ring of the benzoyl group (delta degrees) can rotate almost freely. Electrostatic potential maps were analyzed and showed that the electrostatic orientation effect seems to make an important contribution to the binding of the active compounds to prostaglandin synthase. An electrostatic orientation model of the binding site is proposed. The frontier orbital charge distribution was also described for each compound. On the other hand, steric, electronic and hydrophobic (log P) parameters were calculated and QSAR analysis showed that the most significant parameter for the antiinflammatory activity was the pi-electron density of the HOMO orbital in the second aromatic ring. These results suggest a possible electronic charge transfer between the aromatic fragments and the receptor.

24-Hour Evaluation of the Ocular Distribution of 14C-Labeled Bromfenac Following Topical Instillation into the Eyes of New Zealand White Rabbits

“…The higher the value, the better the penetration, with a 1.0-unit difference in the coefficient representing a tenfold difference in penetration. Ruiz et al 6 reported that the C log P of bromfenac (2.23) is higher than other NSAIDs, such as amfenac (1.23) and ketorolac (1.88). This difference in C log P explains the higher lipophilicity of bromfenac that provides a more rapid saturation of the epithelium and a minimal lag time before the drug crosses the cornea and, thus, the fast analgesic action.…”

“…1 Preclinical data demonstrated that this halogenation of the molecule not only produced greater in vitro and in vivo potency, 2-5 but also enhanced bromfenac absorption across the cornea and penetration in ocular tissues. 6,7 The octanol/water (O/W) partition coefficient (C log P ) and the quantitative structure-activity relationship (QSAR) of a drug is another factor that influences its penetration properties and, consequently, its potency. C log P estimates the water solubility and the level of lipophilicity of a compound (a key determinant of the pharmacokinetics parameter).…”

Ocular Pharmacokinetics of a Single Dose of Bromfenac Sodium Ophthalmic Solution 0.1% in Human Aqueous Humor

“…20 Preclinical data demonstrate that halogenation of the bromfenac molecule increases in vitro and in vivo potency, improves absorption across the cornea, and enhances penetration through the ocular tissues. 21,22 In an in vitro inhibition analysis of IC 50 assays, bromfenac was found to be the most potent inhibitor of the COX-2 enzyme, ranging from 3 to 18 times more potent than the other available ophthalmic NSAIDs (amfenac, diclofenac, and ketorolac). 12,23 Bromfenac sodium ophthalmic solution 0.1% (Bronuck ® ; Senju Pharmaceutical Co., Ltd., Osaka, Japan) received regulatory approval in Japan in 2000 and is indicated for the treatment of ocular inflammatory diseases (blepharitis, conjunctivitis, and scleritis, including episcleritis) and postoperative inflammation.…”

Bromfenac Ophthalmic Solution 0.07 %: A Review of Its Use After Cataract Surgery

“…Its mechanism of action is believed to result from its potent (in the nM range) inhibitory effect on cyclooxygenase (COX)-1 and -2 and, thus, on prostaglandin synthesis [7,9]. The presence of bromine in the bromfenac molecule increases the lipophilicity of bromfenac, with the drug being more lipophilic than amfenac (another NSAID) [partition coefficient (log P) of 2.23 vs. 1.23] [10]. It also increases the drug's potency against COX-1 and COX-2 compared with amfenac [9].…”