Design and syntheses of melanocortin subtype-4 receptor agonists. Part 2: Discovery of the dihydropyridazinone motif

Development of a New Synthesis for the Large-Scale Preparation of Triple Reuptake Inhibitor (−)-GSK1360707

“…Our first attempts at an alternate route to GSK1360707 are shown in Scheme . Suzuki coupling of the conjugated vinyl triflate ( 1 , vide infra ) derived from the commercially available β-ketoester 2 and 3,4-dichlorophenylboronic acid 3 afforded α,β-unsaturated ester 4a (see Scheme for details). Unfortunately, all efforts to convert 4a to the corresponding cyclopropane 5a by reaction with a variety of sulfur ylides or with basic nitromethane failed.…”

Small Molecule Ligands of the Human Melanocortin-4 Receptor

“…Reducing the number of low energy conformations in the C-4 side chain then led to the discovery of pyridazinone 48, a relatively potent and subtype selective partial agonist of the hMC4 receptor. In a subsequent study, we were able to make further enhancements to the pyridazinone design [43]. SAR studies of the aryl piperidine fragment and the pyridazinone core led to the identification of dihydropyridazinone 49, a highly potent and subtype selective full agonist of the hMC4 receptor (Fig.…”

Diverse chemical and biological potentials of various pyridazine and pyridazinone derivatives

“…The SAR of the series of 2-[[4-(substituted-phenyl/benzyl)-1-piperazinyl] methyl]-6-(4methoxyphenyl)-3(2H) pyridazinones is also discussed (Gökçe at al., 2005). The biological activity of a class of nonpeptidyl, pyridazinone derived human melanocortin subtype-4 receptor agonists is disclosed (Ujjainwalla at al., 2005). A series of amide derivatives of [6-(3,5-dimethyl-4-chloropyrazole-1-yl)-3(2H)-pyridazinone-2-yl]acetic acid (48) were tested for their in vivo analgesic and anti-inflammatory activity.…”