QSAR analysis of meclofenamic acid analogues as selective COX-2 inhibitors

Bioorg Med Chem Lett. 2006 Jan 15;16(2):461-8. doi: 10.1016/j.bmcl.2005.07.067. Epub 2005 Nov 14.

Abstract

The use of quantitative structure-activity relationships, since its advent, has become increasingly helpful in understanding many aspects of biochemical interactions in drug research. This approach was utilized to explain the relationship of structure with biological activity of selective COX-2 inhibitors. The enormity of the COX-2 discovery is reflected in the unprecedented speed at which research laboratories have sought to validate its clinical implications. Presented herein is a series of 21 derivatives of meclofenamic acid with selective COX-2 inhibitory activity. Several statistically significant regression expressions were obtained for both COX-1 and COX-2 inhibition using sequential multiple linear regression analysis method. Two of these models were selected and validated further, which revealed the importance of Kier molecular flexibility index for COX-2 inhibitory activity and the number of hydrogen bond donor atoms for COX-1 inhibitory activity. Additionally, linear correlation of molecular flexibility with COX-1 and COX-2 inhibitory activities revealed that flexibility of molecules at COX-2 active site can improve the selectivity of COX-2 inhibitors.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Cyclooxygenase 2 / drug effects*
  • Cyclooxygenase Inhibitors / analysis*
  • Cyclooxygenase Inhibitors / chemistry
  • Cyclooxygenase Inhibitors / pharmacology*
  • Linear Models
  • Meclofenamic Acid / analogs & derivatives*
  • Meclofenamic Acid / chemistry
  • Meclofenamic Acid / pharmacology*
  • Molecular Structure
  • Quantitative Structure-Activity Relationship*

Substances

  • Cyclooxygenase Inhibitors
  • Meclofenamic Acid
  • Cyclooxygenase 2