Identification and pharmacological profile of an indane based series of

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 l...
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Article Cite This: J. Med. Chem. 2018, 61, 5974−5987

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Identification and Pharmacological Profile of an Indane Based Series of Ghrelin Receptor Full Agonists Cristina Gardelli,*,† Hiroki Wada,†,¶ Asim Ray,† Moya Caffrey,† Antonio Llinas,‡ Igor Shamovsky,† Joakim Tholander,⊥,+ Joakim Larsson,†,□ Ulf Sivars,§ Leif Hultin,# Ulf Andersson,∇ Hitesh J. Sanganee,○ Kristina Stenvall,∥ Brith Leidvik,◆,● Karin Gedda,◆ Lisa Jinton,§ Marie Rydeń Landergren,† and Kostas Karabelas∥,■ Downloaded via DURHAM UNIV on July 28, 2018 at 04:49:32 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.



Medicinal Chemistry Department, ‡DMPK Department, §Bioscience Department, ∥Projects Department, Respiratory, Inflammation and Autoimmunity IMED Biotech Unit, AstraZeneca Gothenburg, 43183 Mölndal, Sweden ⊥ Medicinal Chemistry Department, Cardiovascular and Metabolic Diseases IMED Biotech Unit, AstraZeneca Gothenburg, 43183 Mölndal, Sweden # Precision Medicine Laboratories, Precision Medicine and Genomics IMED Biotech Unit, AstraZeneca Gothenburg, 43183 Mölndal, Sweden ∇ Drug Safety and Metabolism IMED Biotech Unit, AstraZeneca Gothenburg, 43183 Mölndal, Sweden ○ Scientific Partnering & Alliances IMED Biotech Unit, AstraZeneca, SK10 4TF Cambridge, United Kingdom ◆ Discovery Sciences IMED Biotech Unit, AstraZeneca Gothenburg, 43183 Mölndal, Sweden S Supporting Information *

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.



INTRODUCTION

secretion of growth hormone (GH, an anabolic hormone that stimulates body growth), enhances gastric motility, and acts on the cardiovascular system to increase cardiac output. With this wide range of biological activities, the ghrelin receptor represents an interesting target for drug discovery. We were particularly interested in the capability of ghrelin to increase endogenous GH and to elevate the plasma level of a second hormone called insulin-like growth factor-1 (IGF-1); consequently, it could have exciting applications in diseases where

Ghrelin is a 28 amino acid peptidic hormone, characterized by a post-translational n-octanoylation on the serine 3 residue. It is synthesized and secreted by X/A-like cells localized within the oxyntic glands of the mucosa of the gastric fundus.1 It is highly conserved across several species, indicating its physiological importance.2 Its pharmacological properties are mediated by the type 1a growth hormone secretagogue receptor (GHS-R1a), a seven transmembrane G-proteincoupled receptor (GPCR) expressed predominantly in the hypothalamus and in the pituitary gland. Ghrelin exhibits several biological activities: it is an orexigenic agent, stimulates © 2018 American Chemical Society

Received: February 27, 2018 Published: June 17, 2018 5974

DOI: 10.1021/acs.jmedchem.8b00322 J. Med. Chem. 2018, 61, 5974−5987

Journal of Medicinal Chemistry

Article

Figure 1. Initial leads in the indane series 1−3 and optimized compound 39.

skeletal muscles are impaired as in cachexia which is associated with many chronic diseases such as cancer, chronic obstructive pulmonary disease (COPD), chronic heart failure, HIV, and many others. The use of ghrelin to reduce cachexia and to increase functional capacity in cachectic patients with COPD has clinical precedence. First, Nagaya et al.3 demonstrated, in an open-label pilot study, that intravenous administration of human ghrelin for 3 weeks to cachectic patients with COPD markedly increased growth hormone secretion, food intake, body weight, lean body mass, peripheral and respiratory muscle strength, the Karnofsky performance status score (a marker for functional capacity), as well as distance walked in 6 min. Later SUN11031,4 a synthetic human ghrelin form, was brought into a phase 2 study where 224 cachectic patients with COPD were treated to determine whether it could enhance body weight, lean body mass, and physical performance. Treatment resulted in a rapid and significant increase in body weight and lean body mass although without significant improvement in functional performance measures. However, subgroup analysis revealed a statistically significant increase in functional performance in subjects with more advanced cachexia. Studies in other chronic disease conditions showed reduced muscle wasting and improved exercise capacity after ghrelin treatment in patients with chronic heart failure.5 Employing exogenous ghrelin administration shows that the half-life of total ghrelin is between 10 and 31 min in the mammalian bloodstream;6 therefore, a number of programs were dedicated to identifying long acting growth hormone secretagogues (GHS) with the potential to increase 24 h IGF-1 levels.7,8 A number of short acting GHSs have been previously described as full agonists of the ghrelin receptor; a few of them have reached advanced clinical stages for cancer cachexia, frailty in the elderly, and gastrointestinal diseases.9−15 A high-throughput screening (HTS) campaign of AstraZeneca’s proprietary collection to identify ghrelin agonists, followed by a hit to lead program, led to the discovery of a series of indane diamides (compounds 1−3) with submicromolar potency (Figure 1, Table 1). This lead series showed partial agonism expressed by the effect of the compounds as a percentage of maximal effect of growth hormone-releasing peptide 6 (GHRP-6). We then embarked on a lead optimization project to switch from partial to full agonism by structural alterations as previously reported for other GPCRs.16,17 Furthermore, we optimized against a poor selectivity of the chemical series toward the hERG channel. Herein, we report our efforts and SAR analysis leading to the identification of compound 39, showing the required pharmacological profile for in vivo studies to predict GH/ IGF-1 activity in humans.

Table 1. Potency in Binding and Functional Assay, Agonism, and Potency in hERG Assay of Compounds 1−7, Ghrelin, Capromorelin, and Ibutamoren binding[a]

functional assay[b]

pIC50

IC50 (μM)

pEC50 and agonism (%)

EC50 (μM)

hERG pIC50[c]

1 2 3 4 5 6 7 ghrelin3

6.4 7.0 6.7 7.8 6.0 7.2 5.9 8.05

0.43 0.098 0.189 0.016 0.93 0.069 1.26 0.009

0.160 0.035 0.047 0.021 0.226 0.10 1.5 0.021

5.8 5.4