Aminothiazole-Featured Pirinixic Acid Derivatives As Dual 5-Lipoxygenase and Microsomal Prostaglandin E₂Synthase-1 Inhibitors with Improved Potency and Efficiency in Vivo

Abstract

Dual inhibition of microsomal prostaglandin E2 synthase-1 (mPGES-1) and 5-lipoxygenase (5-LO) is currently pursued as potential pharmacological strategy for treatment of inflammation and cancer. Here we present a series of 26 novel 2-aminothiazole-featured pirinixic acid derivatives as dual 5-LO/mPGES-1 inhibitors with improved potency (exemplified by compound 16 (2-[(4-chloro-6-{[4-(naphthalen-2-yl)-1,3-thiazol-2-yl]amino}pyrimidin-2-yl)sulfanyl]octanoic acid) with IC50 = 0.3 and 0.4 μM, respectively) and bioactivity in vivo. Computational analysis presumes binding sites of 16 at the tip of the 5-LO catalytic domain and within a subpocket of the mPGES-1 active site. Compound 16 (10 μM) hardly suppressed cyclooxygenase (COX)-1/2 activities, failed to inhibit 12/15-LOs, and is devoid of radical scavenger properties. Finally, compound 16 reduced vascular permeability and inflammatory cell infiltration in a zymosan-induced mouse peritonitis model accompanied by impaired levels of cysteinyl-leukotrienes and prostaglandin E2. Together, 2-aminothiazole-featured pirinixic acids represent potent dual 5-LO/mPGES-1 inhibitors with an attractive pharmacological profile as anti-inflammatory drugs.

Nonsteroidal Anti‐Inflammatory Therapy: A Journey Toward Safety

“…For instance, the substitution of the carboxylic acid moiety of indomethacin, lonazolac, and licofelone by sulfonamide moieties allowed the synthesis of potent dual acting compounds without cross‐reactivity on COX . Moreover, diverse series of pirinixic acid derivatives were designed and evaluated regarding the dual inhibition of mPGES‐1 and 5‐LOX, namely, α‐substituted derivatives, α‐naphtyl derivatives and 2‐aminothiazole derivatives . Among the various pirinixic acid derivatives with dual acting activity, one α‐(n‐hexyl)‐substituted derivative (YS121) and one 2‐aminothiazole derivative have exhibited anti‐inflammatory actions in vivo .…”

Perspective of microsomal prostaglandin E2 synthase-1 as drug target in inflammation-related disorders

“…Comprehensive SAR studies and target-oriented design led to promising leads such as YS121 [101], compound 29 [102] and compound 16 [103] (Table 2) with potent anti-inflammatory efficacy and repression of LT and PGE 2 levels in vivo in relevant animal models (e.g., carrageenan-induce pleurisy in rats, zymosan-induced peritonitis in mice) without marked repression of COX products such as 6-keto PGF 1α . Note that these compounds also repressed anti-inflammatory properties and significantly reduced LTB 4 and PGE 2 levels (but not 6-keto PGF 1α ) in vivo (mouse paw edema and rat pleurisy) [104,105] (Table 2).…”

Aminothiazoles: Hit to lead development to identify antileishmanial agents

“…From the hits identified, 10 scaffolds emerged and the one (aminothiazole) bearing the most appropriate drug-like features was selected for further optimization ( Figure 1). The aminothiazoles, fused aminothiazoles, and other aminothiazoles linked to various heterocyclic rings have recently gained attention for their chemotherapeutic activity for treatment of malaria [13], prion disease [14], antiinflammatory/cancer [15] and tuberculosis [16].…”