A new class of histamine H3 receptor antagonists derived from ligand based design

Roche, Olivier; Sarmiento, Rosa Marı́a Rodrı́guez

doi:10.1016/j.bmcl.2007.04.056

Cited by 35 publications

(20 citation statements)

References 26 publications

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“…In order to design new highly potent and selective nonimidazole inverse agonists for the H 3 R, pharmacophore models from known H 3 R antagonists, including JNJ5207852 or A-349821, for example, were derived [62]. The resulting pharmacophore models consist of positively charged areas, induced by a basic amine moiety, electron rich areas and aromatic/ lipophilic areas.…”

Section: The Histamine H 3 Receptor and Its Ligandsmentioning

confidence: 99%

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Molecular modeling and QSAR-based design of histamine receptor ligands

Straßer

2009

Expert Opinion on Drug Discovery

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There have been several new studies in the past years aimed at developing new histamine receptor ligands on the one hand and at explaining pharmacological profiles on molecular level on the other. For these purposes, not only molecular modeling techniques, but also synthesis, pharmacological characterization, molecular biological and physical techniques are useful. This combination of several different theoretical and experimental techniques allows getting a more detailed insight into the interaction of histamine receptor ligands with histamine receptors and developing new drugs.

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Section: The Histamine H 3 Receptor and Its Ligandsmentioning

confidence: 99%

“…Based on previous pharmacophore models [62], an extended pharmacophore model for H 3 R ligands was generated [63,64]. In addition to the two aromatics, two positively charged features and one electron rich feature, a new acceptor feature was introduced.…”

Section: The Histamine H 3 Receptor and Its Ligandsmentioning

confidence: 99%

Molecular modeling and QSAR-based design of histamine receptor ligands

Straßer

2009

Expert Opinion on Drug Discovery

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“…(6 and 7) in the pharmacophore model, interacting presumably with the ubiquously expressed Asp 3.32 (for definition of the amino acid numbering, see ref. [76]) through a salt bridge [77,78]. An ether or a carbonyl function is present in a large number of potent ligands R1, Fig.…”

Section: Pharmacophore and Homology Modelsmentioning

confidence: 99%

The Histamine H3 Receptor as a Therapeutic Drug Target for Metabolic Disorders: Status, Challenges and Opportunities

Plancher

2011

CTMC

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Since the histamine-3 receptor (H₃R) was cloned in 1999, huge efforts have been made by most of the key players in the pharmaceutical industry as well as in smaller biotech companies to increase the knowledge on this peculiar receptor, with the ultimate goal of bringing new drugs to the market. This review gives a survey on the most valuable chemical tools discovered so far and the significant pharmacological experiments on metabolic disease models published to date. Pharmacology of H₃R antagonists turns out to be very complex due to various functional activities, species selectivity, presence of H₃R isoforms and the poorly understood dichotomy in efficacy between CNS and metabolic disease models. Adding an extra layer of complexity, researchers have to cope with some recurrent safety concerns, some of them being tightly linked to the nature of the H₃R pharmacophore. Therefore this review also strives to summarize the major hurdles and some of the contradictions seen in the H₃R field, together with a brief overview of the clinical trials currently running.

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“…In these examples, different de novo design methods were used for the discovery of ligands of FK506 binding protein-12 (LUDI) [83], thrombin (LUDI) [84], DNA gyrase (LUDI) [85], dihydroorotate dehydrogenase (Sprout) [86], the histamine H3 receptor (SkelGen) [87], creatine kinase (i:lib diverse) [88], cyclin-dependent kinase 4 (Legend) [89] and carbonic anhydrase II (CombiSmoG) [82].…”

Section: De Novo Designmentioning

confidence: 99%

Computational Tools for In Silico Fragment-Based Drug Design

Mortier¹,

Rakers²,

Frédérick³

et al. 2012

CTMC

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Fragment-based strategy in drug design involves the initial discovery of low-molecular mass molecules. Owing to their small-size, fragments are molecular tools to probe specific sub-pockets within a protein active site. Once their interaction within the enzyme cavity is clearly understood and experimentally validated, they represent a unique opportunity to design potent and efficient larger compounds. Computer-aided methods can essentially support the identification of suitable fragments. In this review, available tools for computational drug design are discussed in the frame of fragmentbased approaches. We analyze and review (i) available commercial fragment libraries with respect to their properties and size, (ii) computational methods for the construction of such a library, (iii) the different strategies and software packages for the selection of the fragments with predicted affinity to a given target, and (iv) tools for the in silico linkage of fragments into an actual high-affinity lead structure candidate.

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A new class of histamine H3 receptor antagonists derived from ligand based design

Cited by 35 publications

References 26 publications

Molecular modeling and QSAR-based design of histamine receptor ligands

Molecular modeling and QSAR-based design of histamine receptor ligands

The Histamine H3 Receptor as a Therapeutic Drug Target for Metabolic Disorders: Status, Challenges and Opportunities

Computational Tools for In Silico Fragment-Based Drug Design

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