Stereoselective Synthesis of a MCHr1 Antagonist

Andersen, Denise L.; Storz, Thomas; Liu, Pingli; Wang, Xin; Li, Leping; Fan, Pingchen; Chen, Xiaoqi; Allgeier, Alan M.; Burgos, Alain; Tedrow, Jason S.; Baum, Jean C.; Chen, Ying; Crockett, Rich; Huang, Liang; Syed, Rashid; Larsen, Robert D.; Martinelli, Mike

doi:10.1021/jo701894v

Cited by 30 publications

(15 citation statements)

References 32 publications

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“…[202] Die Robinson-Anellierung von Enamin 364 und (E)-3-Penten-2-on (14)f ührte zur Bildung des gewünschten Addukts in einer Mischung aus vier racemischen Diastereome-Schema 98. Diese Methode wurde für die diastereoselektive Synthese von AMG 076 angewendet, einem Antagonisten von Melanin-konzentrierendem Hormon zur Behandlung von Adipositas (Schema 102).…”

Section: Enantiomerentrennung Von Aminen:t Artratunclassified

“…Diese Methode wurde für die diastereoselektive Synthese von AMG 076 angewendet, einem Antagonisten von Melanin-konzentrierendem Hormon zur Behandlung von Adipositas (Schema 102). [202] Die Robinson-Anellierung von Enamin 364 und (E)-3-Penten-2-on (14)f ührte zur Bildung des gewünschten Addukts in einer Mischung aus vier racemischen Diastereome-Schema 98. Enantiomerentrennungeines Zwischenprodukts der Synthese eines Androstenonderivats.…”

Section: Enantiomerentrennung Von Aminen:t Artratunclassified

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Enantioselektive Synthese von Robinson‐Anellierungsprodukten und Michael‐Addukten als Vorstufen

Gallier

Martel²,

Dujardin³

2017

Angewandte Chemie

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Die Robinson‐Anellierung hat seit ihrer Entdeckung 1935 in zahlreichen Synthesen Anwendung gefunden, besonders auf dem Gebiet der Steroidsynthese. Die Produkte werden gewöhnlich nach drei aufeinanderfolgenden Stufen erhalten: der Bildung eines Enolats (oder Derivats davon), einer konjugierten Addition und einer Aldolreaktion. Im Laufe der Jahre wurden mehrere methodische Verbesserungen für jede einzelne Stufe vorgenommen oder alternative Synthesewege hin zu Robinson‐Anellierungsprodukten entwickelt. Im ersten Teil dieses Aufsatzes werden die wichtigsten Entwicklungen für die Bildung Monocarbonyl‐abgeleiteter Robinson‐Anellierungsprodukte (MRA‐Produkten, MRAPs) und von einer aktivierten Monocarbonylverbindung abgeleiteter Robinson‐Anellierungsprodukte (AMRA‐Produkten, AMRAPs) erläutert. In den folgenden Abschnitten werden diastereoselektive und enantioselektive Synthesen dieser Produkte beschrieben, und im letzten Abschnitt wird die Racematspaltung von Enantiomerenmischungen dargelegt.

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Section: Enantiomerentrennung Von Aminen:t Artratunclassified

Enantioselektive Synthese von Robinson‐Anellierungsprodukten und Michael‐Addukten als Vorstufen

Gallier

Martel²,

Dujardin³

2017

Angewandte Chemie

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“…Among these GW 856464 [211], AMG076 [212] and NGD-4715 [213] achieved phase 1 clinical investigations. Trials to optimize quinazolines [214][215][216][217][218][219], as (40) (Figure 9(a)), revealed GW 803430 (GW3430; [214]), ATC0175 and ATC0065 [215] which were shown efficacious in rodent depression models [197].…”

Section: Non-peptide Ligands Of Mch-receptorsmentioning

confidence: 99%

Non-peptide ligands in the characterization of peptide receptors at the interface between neuroendocrine and mental diseases

Pissarek¹,

Disko²

2013

WJNS

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Hypothalamic receptors for neuropeptide Y, melaninconcentrating hormone, melanocortins and orexins/ hypocretins as well as for the downstream signaling corticotrophic factor have been discussed broadly for their influence on food intake and reward but also on several psychiatric disorders. For the development of non-peptide ligands for the in vivo detection of alterations in density and affinity of such G-protein coupled (GPCRs) peptide receptors the requirements to affinity and pharmacokinetics have been shifted to thresholds markedly distict from classical GPCRs to dissociation constants < 0.5 nM, partition coefficients log P < 3.5 and transcellular transport ratios, e.g. for the permeability glycoprotein transporter, below 3. Nevertheless, a multitude of compounds has been reported originally as potential therapeutics in the treatment of obesity among which some are suitable candidates for labeling as PET or SPECT-tracers providing receptor affinities even below 0.1 nM. These could be unique tools not only for better understanding of the mechanism of obesity but also for investigations of extrahypothalamic role of "feeding receptors" at the interface between neuroendocrine and mental diseases.

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“…[13][14][15][16] In the last decade, extensive research by numerous pharmaceutical companies and academic groups have led to the identification of a variety of pharmacophore derivatives of MCH-R1 antagonists as potential anti-obesity agents. To date, few candidates including GW856464, 17,18) AMG-076, 19) NGD-4715, 20,21) ALB-127158, [22][23][24] and BMS-830216, 25) a prodrug of BMS-819881 (structure undisclosed) have advanced to the phase 1 clinical stage owing to their unsuitable pharmacokinetic (PK) profiles and safety concerns [26][27][28] (Fig. 1).…”

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confidence: 99%

Synthesis and Structure–Activity Relationship of Naphtho[1,2-<i>b</i>]furan-2-carboxamide Derivatives as Melanin Concentrating Hormone Receptor 1 Antagonists

Lim

Choi

Lee

et al. 2013

CHEMICAL & PHARMACEUTICAL BULLETIN

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The discovery that novel naphtho[1,2-b]furan-2-carboxamides containing linked piperidinylphenylacetamide groups serve as melanin concentrating hormone receptor 1 (MCH-R1) antagonists is described. An extensive structure-activity relationship (SAR) study, probing members of this family that contain a variety of aryl and heteroaryl groups at C-5 of the naphtho[1,2-b]furan-2-carboxamide skeleton and having different chain linker lengths, led to the identification of the 5-(4-pyridinyl) substituted analog 10b as a highly potent MCH-R1 antagonist with an IC 50 value of 3 nM. This substance also displays good metabolic stability and it does not significantly inhibit cytochrome P450 (CYP450) enzymes. However, 10b has unacceptable oral bioavailability.Key words melanin concentrating hormone (MCH); MCH-receptor 1 antagonist; obesity; naphtho[1,2-b]-furan-2-carboxamide Obesity, occurring because of an imbalance between energy intake and expenditure, is rapidly increasing worldwide and has become nearly a global epidemic. 1) Moreover, obesity is a major risk factor associated with a number of severe diseases, including type 2 diabetes, dyslipidemia, coronary heart disease, stroke and certain cancers.2) Many biological targets for treating obesity have been evaluated, including prevention of fat absorption, modulation of fat metabolism or storage, increase of thermogenesis, and modulation of central satiety and hunger regulating systems.3,4) Among several centrally acting targets, the melanin concentrating hormone (MCH) has received great attention as a target for obesity treatment. MCH, an orexigenic cyclic 19-amino acid polypeptide, is expressed predominantly in the lateral hypothalamus of the brain and is known to play a physiological role in both the regulation of feeding and energy homeostasis. 5,6) The effects of this peptide are mediated through its interaction with two types of G protein-coupled receptors called MCH-receptor 1 and 2 (MCH-R1 and -R2). 7,8) While the exact biological functions of MCH-R2 are still unknown, those of MCH-R1 have been demonstrated in previous genetic and pharmacological studies. Genetically altered mice that lack the gene encoding MCH-R1 maintain elevated metabolic rates and remain lean despite hyperphagia on a normal diet. 9) Specifically, the results of these efforts have shown that MCH-R1 plays an essential role in the control of food intake and body weight.9-12) As a consequence of these properties, MCH-R1 is considered to be one of the most promising targets for treating obesity, though it still remains to be seen whether this translates to safe clinical efficacy in humans.Numerous MCH-R1 antagonists have been found to have anti-obesity efficacy in diet-induced obesity (DIO) animal models. [13][14][15][16] In the last decade, extensive research by numerous pharmaceutical companies and academic groups have led to the identification of a variety of pharmacophore derivatives of MCH-R1 antagonists as potential anti-obesity agents. To date, few candidates including GW856464, 17,18) AMG-07...

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Stereoselective Synthesis of a MCHr1 Antagonist

Cited by 30 publications

References 32 publications

Enantioselektive Synthese von Robinson‐Anellierungsprodukten und Michael‐Addukten als Vorstufen

Enantioselektive Synthese von Robinson‐Anellierungsprodukten und Michael‐Addukten als Vorstufen

Non-peptide ligands in the characterization of peptide receptors at the interface between neuroendocrine and mental diseases

Synthesis and Structure–Activity Relationship of Naphtho[1,2-<i>b</i>]furan-2-carboxamide Derivatives as Melanin Concentrating Hormone Receptor 1 Antagonists

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