Structure–activity relationships of a novel series of melanin-concentrating hormone (MCH) receptor antagonists

Arienzo, Rosa; Clark, David E.; Cramp, Sue; Daly, Stephen; Dyke, Hazel J.; Lockey, Peter; Norman, Dennis; Roach, A. G.; Stuttle, K.A.J.; Tomlinson, Maxine; Wong, Melanie; Wren, Stephen P.

doi:10.1016/j.bmcl.2004.05.051

Cited by 40 publications

(7 citation statements)

References 8 publications

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“…Hit-to-lead chemistry exploration around this compound will be reported elsewhere. 30 An analysis of the virtual screening results confirmed the conventional wisdom of utilizing as many query compounds and search techniques as possible in order to maximize the chances of finding hits.…”

Section: Discussionmentioning

confidence: 74%

“…As well as being a reasonably potent antagonist at the MCH-1R, compound 12 has attractive computed physicochemical properties (MW = 424.9, PSA = 64.5 Å 2 , ClogP = 4.47) together with some obvious synthetic disconnections. It was thus considered to be an excellent starting point for hit-to-lead optimization studies 2 Most potent compound identified by the initial round of virtual screening. 2 Early SAR Data from the First Round of Compound Screenings

…”

Section: Biochemical Screening Resultsmentioning

confidence: 99%

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A Virtual Screening Approach to Finding Novel and Potent Antagonists at the Melanin-Concentrating Hormone 1 Receptor

et al. 2004

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Melanin-concentrating hormone (MCH) has been known to be an appetite-stimulating peptide for a number of years. However, it is only recently that MCH has been discovered to be the natural ligand for a previously "orphan" G-protein-coupled receptor, now designated MCH-1R. This receptor has been shown to mediate the effects of MCH on appetite and body weight, and consequently, drug discovery programs have begun to exploit this information in the search for MCH-1R antagonists for the treatment of obesity. In this paper, we report the rapid discovery of multiple, structurally distinct series of MCH-1R antagonists using a variety of virtual screening techniques. The most potent of these compounds (12) demonstrated an IC(50) value of 55 nM in the primary screen and exhibited antagonist properties in a functional cellular assay measuring Ca(2+) release. More potent compounds were identified by follow-up searches around the initial hit. A proposed binding mode for compound 12 in a homology model of the MCH-1R is also presented.

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Section: Discussionmentioning

confidence: 74%

…”

Section: Biochemical Screening Resultsmentioning

confidence: 99%

A Virtual Screening Approach to Finding Novel and Potent Antagonists at the Melanin-Concentrating Hormone 1 Receptor

et al. 2004

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“…For example, piperidine analogue 36 and morpholine analogues 37 and 48 (Table ) all exhibited affinities close to that of 22 . The redundancy of the basic amine was also noted by the Argenta group, although they found a piperidine analogue to be less potent 22b2 Influence of Alkyl Substituents in the Central Part of the Molecule a Whole-cell binding to MCH1R.…”

Section: Resultsmentioning

confidence: 68%

“…In the present paper we describe an efficient chemotype jump using this SAR knowledge to construct 3D pharmacophores that are used for in silico screening of commercial compound libraries and subsequent optimization of the identified quinoline compounds . It is notable that this compound series was also independently discovered by Clark and co-workers using different virtual screening approaches based on 11 compounds from the public domain . However, in their case the 3D pharmacophore search did not produce any hits, and the quinolines were identified by other search strategies.…”

Section: Introductionmentioning

confidence: 86%

6-Acylamino-2-aminoquinolines as Potent Melanin-Concentrating Hormone 1 Receptor Antagonists. Identification, Structure−Activity Relationship, and Investigation of Binding Mode

Ulven¹,

Frimurer²,

Receveur³

et al. 2005

J. Med. Chem.

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Novel 6-acylamino-2-aminoquinoline melanin-concentrating hormone 1 receptor (MCH1R) antagonists were identified by sequential in silico screening with 3D pharmacophore models derived from a series of benzamide antagonists. The structure-activity relationship exploration by synthesis of analogues found structural demands around the western part of the compounds to be quite specific, whereas much structural freedom was found in the eastern part. While these compounds in general suffered from poor solubility properties, the 4-trifluoromethoxyphenoxyacetamide western appendage provided a favorable combination of activity and solubility properties. The amine in the eastern appendage, originally required by the pharmacophore model and believed to interact with Asp123 in transmembrane 3 of MCH1R, could be removed without diminishing affinity or functional activity of the compounds. Docking studies suggested that the Asp123 interacts preferentially with the nitrogen of the central quinoline. Synthesis and testing of specific analogues supported our revised binding mode hypothesis.

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“…Figure 24) antagonist with an IC 50 of 1.9 ± 0.4 nM, suggesting that the aromatic ring is coplanar with the quinoline system. The redundancy of the basic amine was also noted by the Argenta Group, although they found a piperidine analogue to be less potent, 73 corroborating the idea that the electron donating property of the 2-amino group is more important that any specific direct interaction with the binding site. Figure 25) in disclosed MCH-R1 antagonists which contained a basic amine group and two aromatic groups joined by an appropriate linker.…”

Section: Figure 16 Compounds 16 and 17mentioning

confidence: 55%

MCH-R1 Antagonists as Potential Anti-obesity Drugs. Design Strategies and Structure-activity Relationship

Rivera¹,

Moreno²,

Bocanegra-García³

2013

Revista Virtual De Química

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Resumo:A obesidade é uma doença crônica que é caracterizada por um acúmulo de excesso de tecido adiposo. Atualmente, existem alguns medicamentos seguros e eficazes para o tratamento farmacológico da obesidade. Portanto, torna-se necessário o desenvolvimento de novas drogas. Na última década, o alvo mais promissor para a obesidade foi o hormônio concentrador de melanina. Com isso, diversas indústrias farmacêuticas desenvolveram peptídeos e pequenas moléculas como antagonistas MCH-R1, mas estes compostos apresentaram problemas como afinidade para o canal hERG e perfil farmacocinético pobre. Neste artigo, fizemos uma breve revisão da concepção da estratégia mais relevante e relações da estrutura-atividade no desenvolvimento de carboxamida, ureias, quinolina e derivados quinazolina como antagonistas MCH-R1. Palavras-chave:Antagonistas; hormônio concentrador de melanina; obesidade. AbstractObesity is a chronic disease that is characterized by an accumulation of excess adipose tissue. Actually, there are few safe and effective drugs for pharmacological treatment of obesity. Therefore, it becomes necessary the development of new drugs. In the last decade, the most promising target for obesity was melanin-concentrating hormone. Thereat, diverse pharmaceutical companies developed peptides and small molecules as MCH-R1 antagonists, but, these compounds had problems as affinity for hERG channel and poor pharmacokinetic profile. In this manuscript, we made a brief review of the most relevant strategy design and structure-activity relationships in the development of carboxamide, ureas, quinoline, and quinazoline derivatives as MCH-R1 antagonists.

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Structure–activity relationships of a novel series of melanin-concentrating hormone (MCH) receptor antagonists

Cited by 40 publications

References 8 publications

A Virtual Screening Approach to Finding Novel and Potent Antagonists at the Melanin-Concentrating Hormone 1 Receptor

A Virtual Screening Approach to Finding Novel and Potent Antagonists at the Melanin-Concentrating Hormone 1 Receptor

6-Acylamino-2-aminoquinolines as Potent Melanin-Concentrating Hormone 1 Receptor Antagonists. Identification, Structure−Activity Relationship, and Investigation of Binding Mode

MCH-R1 Antagonists as Potential Anti-obesity Drugs. Design Strategies and Structure-activity Relationship

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