Discovery, synthesis, and structure–activity relationship of 6-aminomethyl-7,8-dihydronaphthalenes as human melanin-concentrating hormone receptor 1 antagonists

Yamashita, Toshiro; Imaeda, Toshihiro; Tanaka, Toshio; Terauchi, Jun; Miyamoto, Maki; Ora, Taiichi; Tawada, Michiko; Endo, Satoshi; Takekawa, Shiro; Asami, Asano; Suzuki, Nobuhiro; Nagisa, Yasutaka; Nakano, Yukiko I.; Watanabe, Kaoru; Ogino, Hitomi; Kato, Kanefusa; Kato, Keita; Ishihara, Yuji

doi:10.1016/j.bmc.2011.07.038

Cited by 10 publications

(14 citation statements)

References 29 publications

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“…Since we first identified MCH as an endogenous ligand for MCHR1 − and discovered the small-molecule antagonist T-226296 ( 1 , (−) enantiomer), a wide variety of potent small-molecule MCHR1 antagonists have been identified by our group (Figure ). − The structures can be described around a central amide with a left-hand side (LHS) and a right-hand side (RHS), which consists of a bicyclic and an aliphatic amine motif. A docking study of tetraline derivative 1 with a homology model based on bovine rhodopsin suggested that the central carbonyl group interacts with Gln127 and the aliphatic amine in the RHS interacts with Asn294 .…”

Section: Introductionmentioning

confidence: 99%

“… − The structures can be described around a central amide with a left-hand side (LHS) and a right-hand side (RHS), which consists of a bicyclic and an aliphatic amine motif. A docking study of tetraline derivative 1 with a homology model based on bovine rhodopsin suggested that the central carbonyl group interacts with Gln127 and the aliphatic amine in the RHS interacts with Asn294 . Although these small-molecule MCHR1 antagonists exert potent anorectic effects on obese animal models toxicological concerns such as hERG inhibition and phospholipidosis limit their clinical potential.…”

Section: Introductionmentioning

confidence: 99%

“…Indeed, we recently reported that introducing substituents near the cationic site effectively reduced hERG inhibition . In some cases, the aliphatic amine could be replaced with other functional groups such as amides and carbamates without loss of affinity for MCHR1 . These amine variants had high selectivity over hERG; however, all were devoid of in vivo efficacy potentially due to lower CNS availability.…”

Section: Introductionmentioning

confidence: 99%

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Melanin-Concentrating Hormone Receptor 1 Antagonists Lacking an Aliphatic Amine: Synthesis and Structure–Activity Relationships of Novel 1-(Imidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one Derivatives

et al. 2016

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Aiming to discover melanin-concentrating hormone receptor 1 (MCHR1) antagonists with improved safety profiles, we hypothesized that the aliphatic amine employed in most antagonists reported to date could be removed if the bicyclic motif of the compound scaffold interacted with Asp123 and/or Tyr272 of MCHR1. We excluded aliphatic amines from our compound designs, with a cutoff value of pK(a) < 8, and explored aliphatic amine-free MCHR1 antagonists in a CNS-oriented chemical space limited by four descriptors (TPSA, ClogP, MW, and HBD count). Screening of novel bicyclic motifs with high intrinsic binding affinity for MCHR1 identified the imidazo[1,2-a]pyridine ring (represented in compounds 6a and 6b), and subsequent cyclization of the central aliphatic amide linkage led to the discovery of a potent, orally bioavailable MCHR1 antagonist 4-[(4-chlorobenzyl)oxy]-1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one 10a. It exhibited low potential for hERG inhibition and phospholipidosis induction as well as sufficient brain concentration to exert antiobesity effects in diet-induced obese rats.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Melanin-Concentrating Hormone Receptor 1 Antagonists Lacking an Aliphatic Amine: Synthesis and Structure–Activity Relationships of Novel 1-(Imidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one Derivatives

et al. 2016

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“…To the best of our knowledge so far [ 29 , 32 , 38 , 39 , 42 , 43 , 46 , 47 , 48 , 49 , 50 , 51 ], two MCHR1 binding pockets (listed as P1 and P2, respectively) have been proposed. P1 represents the conventional binding cavity that almost all docking researches have referred to where a typical interaction of salt bridge is found experimentally formed by Asp123, and simultaneously H-bond or hydrophobic regions may also be embodied.…”

Section: Resultsmentioning

confidence: 99%

Profiling the Interaction Mechanism of Quinoline/Quinazoline Derivatives as MCHR1 Antagonists: An in Silico Method

et al. 2014

IJMS

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Melanin concentrating hormone receptor 1 (MCHR1), a crucial regulator of energy homeostasis involved in the control of feeding and energy metabolism, is a promising target for treatment of obesity. In the present work, the up-to-date largest set of 181 quinoline/quinazoline derivatives as MCHR1 antagonists was subjected to both ligand- and receptor-based three-dimensional quantitative structure–activity (3D-QSAR) analysis applying comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). The optimal predictable CoMSIA model exhibited significant validity with the cross-validated correlation coefficient (Q2) = 0.509, non-cross-validated correlation coefficient (R2ncv) = 0.841 and the predicted correlation coefficient (R2pred) = 0.745. In addition, docking studies and molecular dynamics (MD) simulations were carried out for further elucidation of the binding modes of MCHR1 antagonists. MD simulations in both water and lipid bilayer systems were performed. We hope that the obtained models and information may help to provide an insight into the interaction mechanism of MCHR1 antagonists and facilitate the design and optimization of novel antagonists as anti-obesity agents.

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“…Many of the resulting optimized lead compounds, representing a diverse set of non-peptide MCHR1 antagonists, have been evaluated in vivo . Non-peptide MCHR1 antagonists are effective in different models of acute food intake in a variety of different rodent strains (Table 2) (Borowsky et al, 2002; Takekawa et al, 2002; Huang et al, 2005; Palani et al, 2005; McBriar et al, 2006; Sasikumar et al, 2006; Xu et al, 2006; Balavoine et al, 2007; Kowalski and Sasikumar, 2007; Moriya et al, 2009; Nagasaki et al, 2009; Haga et al, 2011; Kamata et al, 2011; Kasai et al, 2011, 2012). In general, MCHR1 antagonists potently block up to 75% of MCH-induced food intake (Borowsky et al, 2002; Takekawa et al, 2002; Moriya et al, 2009; Nagasaki et al, 2009), but they have more modest effects on reducing fasting-induced feeding and spontaneous feeding.…”

Section: Pharmacologic Studies Confirm a Role For Mch In Energy Homeomentioning

confidence: 99%

The Role of Melanin-Concentrating Hormone and Its Receptors in Energy Homeostasis

MacNeil¹

2013

Front. Endocrinol.

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Extensive studies in rodents with melanin-concentrating hormone (MCH) have demonstrated that the neuropeptide hormone is a potent orexigen. Acutely, MCH causes an increase in food intake, while chronically it leads to increased weight gain, primarily as an increase in fat mass. Multiple knockout mice models have confirmed the importance of MCH in modulating energy homeostasis. Animals lacking MCH, MCH-containing neurons, or the MCH receptor all are resistant to diet-induced obesity. These genetic and pharmacologic studies have prompted a large effort to identify potent and selective MCH receptor antagonists, initially as tool compounds to probe pharmacology in models of obesity, with an ultimate goal to identify novel anti-obesity drugs. In animal models, MCH antagonists have consistently shown efficacy in reducing food intake acutely and inhibiting body-weight gain when given chronically. Five compounds have proceeded into clinical testing. Although they were reported as well-tolerated, none has advanced to long-term efficacy and safety studies.

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Discovery, synthesis, and structure–activity relationship of 6-aminomethyl-7,8-dihydronaphthalenes as human melanin-concentrating hormone receptor 1 antagonists

Cited by 10 publications

References 29 publications

Melanin-Concentrating Hormone Receptor 1 Antagonists Lacking an Aliphatic Amine: Synthesis and Structure–Activity Relationships of Novel 1-(Imidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one Derivatives

Melanin-Concentrating Hormone Receptor 1 Antagonists Lacking an Aliphatic Amine: Synthesis and Structure–Activity Relationships of Novel 1-(Imidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one Derivatives

Profiling the Interaction Mechanism of Quinoline/Quinazoline Derivatives as MCHR1 Antagonists: An in Silico Method

The Role of Melanin-Concentrating Hormone and Its Receptors in Energy Homeostasis

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