Synthesis of substituted benzamides as anti-inflammatory agents that inhibit preferentially cyclooxygenase 1 but do not cause gastric damage

G Caliendo; V Santagada; E Perissutti; B Severino; F Fiorino; T D Warner; J L Wallace; D R Ifa; E Antunes; G Cirino; G de Nucci

doi:10.1016/s0223-5234(01)01251-x

Synthesis of substituted benzamides as anti-inflammatory agents that inhibit preferentially cyclooxygenase 1 but do not cause gastric damage

Eur J Med Chem. 2001 Jun;36(6):517-30. doi: 10.1016/s0223-5234(01)01251-x.

Authors

G Caliendo¹, V Santagada, E Perissutti, B Severino, F Fiorino, T D Warner, J L Wallace, D R Ifa, E Antunes, G Cirino, G de Nucci

Affiliation

¹ Dipartimento di Chimica Farmaceutica e Tossicologica, Università di Napoli Federico II, Via Domenico Montesano 49, I-80131, Naples, Italy. caliendo@unina.it

PMID: 11525842
DOI: 10.1016/s0223-5234(01)01251-x

Abstract

Parsalmide (5-amino-N-butyl-2-(2-propynyloxy) benzamide) (5a), is a non-steroidal anti-inflammatory drug (NSAID), commercialised in Italy until 1985 with the brand name of Synovial(R), that has been widely used to treat arthritic patient. In addition, it was shown to spare gastric mucosa. Here we have synthesised a series of novel substituted benzamides, related to Parsalmide, and have evaluated their activity in vitro on COX-1 and COX-2 as well as in vivo in the carrageenin-induced rat paw edema, a classical in vivo anti-inflammatory assay. Compounds 5b, 11a and 11b, which showed a favourable profile in vitro and in vivo, were screened in comparison with Parsalmide for gastrointestinal (GI) tolerability in vivo in the rat. Results obtained showed that Parsalmide and compound 11b inhibited both COX-1 and COX-2 in vitro as well as they were active in vivo. Both compounds were devoid of gastric effect at the efficacious dose. In addition, both prevented indomethacin-induced gastric damage. Thus, these compounds may guide the definition of a new leading structure with anti-inflammatory activity that may allow designing new safer NSAIDs.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Anti-Inflammatory Agents / adverse effects
Anti-Inflammatory Agents / chemical synthesis*
Anti-Inflammatory Agents / chemistry
Anti-Inflammatory Agents / pharmacology*
Benzamides / adverse effects
Benzamides / chemical synthesis*
Benzamides / chemistry
Benzamides / pharmacology*
Cyclooxygenase 1
Cyclooxygenase 2
Cyclooxygenase 2 Inhibitors
Cyclooxygenase Inhibitors / adverse effects
Cyclooxygenase Inhibitors / chemical synthesis*
Cyclooxygenase Inhibitors / chemistry
Cyclooxygenase Inhibitors / pharmacology
Drug Design
Drug Evaluation, Preclinical
Edema / chemically induced
Edema / drug therapy
Food Deprivation
Inhibitory Concentration 50
Isoenzymes / antagonists & inhibitors*
Isoenzymes / metabolism
Magnetic Resonance Spectroscopy
Male
Membrane Proteins
Prostaglandin-Endoperoxide Synthases / metabolism
Rats
Rats, Wistar
Sheep
Stomach / drug effects*
Stomach / pathology
Structure-Activity Relationship
Substrate Specificity

Substances

Anti-Inflammatory Agents
Benzamides
Cyclooxygenase 2 Inhibitors
Cyclooxygenase Inhibitors
Isoenzymes
Membrane Proteins
Cyclooxygenase 1
Cyclooxygenase 2
Prostaglandin-Endoperoxide Synthases
Ptgs1 protein, rat