Synthesis and Pharmacological Characterization of Novel Druglike Corticotropin-Releasing Factor 1 Antagonists

Abstract

To identify new CRF(1) receptor antagonists, an attempt to modify the bis-heterocycle moiety present in the top region of the dihydropyrrole[2,3]pyridine template was made following new pharmacophoric hypothesis on the CRF(1) receptor antagonists binding pocket. In particular, the 2-thiazole ring, present in the previous series of compounds, was replaced by more hydrophilic non aromatic heterocycles able to make appropriate H-bond interactions with amino acid residues Thr192 and Tyr195. This exploration, followed by an accurate analysis of the substitution of the pendant aryl ring, enabled to identify in vitro potent compounds showing excellent pharmacokinetics and outstanding in vivo activity in animal models of anxiety, both in rodents and primates.

The CRH1 Antagonist GSK561679 Increases Human Fear But Not Anxiety as Assessed by Startle

“…It is a safe, orally active, potent, and highly selective antagonist at the CRF 1 receptor with good brain penetration and good in vitro and metabolic stability (Dunlop et al, 2014). GSK561679 has anxiolytic-like effects in the human threat test in marmosets (Fabio et al, 2008), but in humans it showed no efficacy in a major depression trial (Protocol no. CRS106139).…”

Methods for the synthesis of 1-substituted 1H-imidazol-2(3H)-ones

“…Ureidoacetals 6 may be obtained by interaction of α-aminоacetals 9 with isocyanates 10 (method I) 25 The obtained ureidoacetals 6 underwent cyclization to the imidazolone 1 in the presence of various acids, including hydrochloric, 1,25,27,28,30,31,[34][35][36][40][41][42][43][44]47 trifluoroacetic, 26,29 acetic, 32,48 formic, 33,37,45 and sulfuric acid 38,39 (Scheme 4).…”

“…The synthesis of compounds 1 was achieved by reaction of α-aminoacetals 9a,b with amides 11 in THF, 37 EtO(CH 2 ) 2 OH, 38 pyridine, 40,44 or MeCN 41,42 media. The obtained ureidoacetals 6 were cyclized in the presence of formic 37,45 or hydrochloric 1,41-44 acid.…”

Synthesis of substituted terpyridine ligands for use in protein purification

“…d 120 ppm) was only observed when the delay time, D1, was set to 15 s and this was only done with the methoxy compound 6c. Reaction of the parent triflate 6a and its methyl homologue 6b with potassium iodide 19 in DMF at 160 C for 2 h gave the corresponding C-4 0 iodides 7a and 7b in excellent yield ( Table 2, entries 1and 2).…”