Identification and Pharmacological Profile of an Indane Based Series of Ghrelin Receptor Full Agonists

Abstract

Cachexia and muscle wasting are very common among patients suffering from cancer, chronic obstructive pulmonary disease, and other chronic diseases. Ghrelin stimulates growth hormone secretion via the ghrelin receptor, which subsequently leads to increase of IGF-1 plasma levels. The activation of the GH/IGF-1 axis leads to an increase of muscle mass and functional capacity. Ghrelin further acts on inflammation, appetite, and adipogenesis and for this reason was considered an important target to address catabolic conditions. We report the synthesis and properties of an indane based series of ghrelin receptor full agonists; they have been shown to generate a sustained increase of IGF-1 levels in dog and have been thoroughly investigated with respect to their functional activity.

Advances in the Development of Nonpeptide Small Molecules Targeting Ghrelin Receptor

“…A high-throughput screening (HTS) approach on AstraZeneca’s library, followed by hit to lead generation, led to the discovery of a series of indane diamides behaving as GHS-R1a partial agonists ( 8 – 10 ) with submicromolar potency ( Figure 8 A). 59 From a subsequent lead optimization strategy, an interesting modulation of the biological profile from partial to full agonism was obtained. In particular, an extensive SAR study led to the identification of the potent druglike GHS-R1a full agonist 11 (EC 50 = 1.6 nM; E max = 89%) ( Figure 8 A), 59 which was devoid of significant hERG channel inhibition.…”

“… 59 From a subsequent lead optimization strategy, an interesting modulation of the biological profile from partial to full agonism was obtained. In particular, an extensive SAR study led to the identification of the potent druglike GHS-R1a full agonist 11 (EC 50 = 1.6 nM; E max = 89%) ( Figure 8 A), 59 which was devoid of significant hERG channel inhibition. This compound showed adequate pharmacokinetic (PK) profile, displaying long half-life and limited brain penetration and increased insulin-like growth factor-1 (IGF-1) secretion in dogs.…”

β‐Trifluoromethyl α,β‐unsaturated Ketones: Efficient Building Blocks for Diverse Trifluoromethylated Molecules

“…Indanes and its derivatives are found in various natural products and biological active molecules, [84] particularly, the aminoindane derivatives are pharmaceutically important candidates [85] . To incorporate the trifluoromethyl group in aminoindane scaffold, recently Sharma and coworkers reported the first synthesis of the 1‐(trifluoromethyl)‐1 H ‐inden‐3‐amine scaffolds 139 using Rh(III)‐catalysed [3+2] C−H annulation reaction of benzimidates 138 with β ‐(trifluoromethyl)‐ α , β ‐unsaturated ketones 3 .…”

Catalyst-Controlled Regioselective Chlorination of Phenols and Anilines through a Lewis Basic Selenoether Catalyst

“…The NMR spectra match the literature precedence. 47 1,2-Dimesityldiselane. N-Bromosuccinimide (2.2 g, 1 equiv) and selenium metal powder (1.2 g 1.2 equiv) were added to a roundbottom flask, and then MeCN (∼60 mL, 0.2 M) was added to the mixture and stirred at 60 °C for 10 min.…”