Identification and hit-to-lead exploration of a novel series of histamine H4 receptor inverse agonists

Cramp, Sue; Dyke, Hazel J.; Higgs, Christopher; Clark, David E.; Gill, Matthew; Savy, Pascal; Jennings, Neil; Price, Steve; Lockey, Peter; Norman, Dennis; Porres, Soraya S.; Wilson, Francis X.; Jones, Alison L; Ramsden, Nigel G.; Mangano, Raffaella; Leggate, Dan; Andersson, Marcus; Hale, Richard

doi:10.1016/j.bmcl.2010.02.097

Cited by 26 publications

(25 citation statements)

References 11 publications

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“…It should be noted that compounds 9a-c (Table 2 and Fig. 7) is similar to the H 4 R scaffold discovered by Cramp et al 80 in an independent ligand-based virtual screening campaign. It should be emphasized however that the compounds discovered in this ligandbased screening were not yet included in the ChEMBLdb database 77 version used in our study, 101 and therefore were identified after completion of our own prospective structurebased virtual screening study.…”

Section: R Ligandsmentioning

confidence: 95%

“…103 This is supported by the fact that 41% of the actives and 21% of the inactives share an imidazole ring with histamine. It should be noted that in a 3D-LBVS campaign, using JNJ7777120 (2) as the reference compound, new H 4 R ligands were discovered 80 that are similar to the experimentally confirmed hits 9a-c that were independently identified in our prospective SBVS study. These hit compounds from Cramp et al were, however, not yet published when we performed our virtual screening and were therefore also not yet included in the ChEMBL database 77 version (downloaded on August 19, 2010) used in our study for the novelty assessment.…”

Section: 99mentioning

confidence: 99%

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Structure-based virtual screening for fragment-like ligands of the G protein-coupled histamine H₄receptor

et al. 2015

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We have explored the possibilities and challenges of structure-based virtual screening (SBVS) against the human histamine H 4 receptor (H 4 R), a key player in inflammatory responses. Several SBVS strategies, employing different H 4 R ligand conformations, were validated and optimized with respect to their ability to discriminate small fragment-like H 4 R ligands from true inactive fragments, and compared to ligand-based virtual screening (LBVS) approaches. SBVS studies with a molecular interaction fingerprint (IFP) scoring method enabled the identification of H 4 R ligands that were not identified in LBVS runs, demonstrating the scaffold hopping potential of combining molecular docking and IFP scoring. Retrospective VS evaluations against H 4 R homology models based on the histamine H 1 receptor (H 1 R) crystal structure did not give higher enrichments of H 4 R ligands than H 4 R models based on the beta-2 adrenergic receptor (β 2 R). Complementary prospective SBVS studies against β 2 R-based and H 1 R-based H 4 R homology models led to the discovery of different new fragment-like H 4 R ligand chemotypes. Of the 37 tested compounds, 9 fragments (representing 5 different scaffolds) had affinities between 0.14 and 6.3 μM at the H 4 R.

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Section: R Ligandsmentioning

confidence: 95%

Section: 99mentioning

confidence: 99%

Structure-based virtual screening for fragment-like ligands of the G protein-coupled histamine H₄receptor

et al. 2015

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“…Selective H 4 -receptor agonists and antagonists have been developed to further characterize the role of the H 4 -receptor [55,56]. A particular focus has been the anti-inflammatory effects of antagonists, with special emphasis on the H 4 -selective drug JNJ-7777120 (Johnson & Johnson, New Brunswick, NJ) [57].…”

Section: Steroids and Nsaidsmentioning

confidence: 99%

Antihistamines in Ocular Allergy: Are They All Created Equal?

Abelson

McLaughlin

Gomes

2011

Curr Allergy Asthma Rep

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Use of topical antihistamines in the treatment of allergic conjunctivitis has evolved over the past several decades as our knowledge of the nature of the underlying disease has progressed. Formulations for the eye typically employ H(1)-receptor antagonists with a dual action, both directly as competitors for histamine receptor occupancy and as mast cell-stabilizing agents. Many of these compounds also display activity against late-phase allergic symptoms. Of the newest available drugs, several have a prolonged duration of action allowing once-daily dosing. Future development is likely to focus on long-acting agents such as these and on drugs that can target additional histamine receptor subtypes.

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“…The histamine GPCRs signal through Gi/o proteins leading to inhibition of cAMP formation, mobilisation of calcium from intracellular stores and stimulation of MAP kinase in both heterologous expression systems and native immune cells [5,6]. H3 and H4 receptors remain highly attractive targets for drug discovery and medicinal chemistry development programs [7][8][9][10]. While the H3 receptor seems to be an interesting target for treatment of certain CNS disorders like cognitive disorders, narcolepsy, ADHD and pain [11,12], the H4 receptor plays an important role inflammation and allergy [13].…”

Section: Introductionmentioning

confidence: 99%

“…In the light of this wide clinical evidence of the importance of H3 and H4 receptors as potential drug targets [7][8][9][10], the need for exploration of the key structural features and key residues involved in antagonist binding and selectivity cannot be overestimated. Such structural data entry 2RH1), human A2A adenosine receptor (A2A, PDB entry 3EML) and bovine rhodopsin (PDB entry 1F88) -the more recently published crystal structure of the histamine 1 (H1) receptor [56] was not available at the time of this work, using a multiple-sequence alignment tool implemented in MOE version 2010.10 (Chemical Computing Group).…”

Section: Introductionmentioning

confidence: 99%

From Receptors to Ligands: Fragment-assisted Drug Design for GPCRs Applied to the Discovery of H3 and H4 Receptor Antagonists

Àlex¹,

Heifetz²,

Mazanetz³

et al. 2013

Med chem

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G-Protein Coupled Receptors (GPCRs) have enormous physiological and biomedical importance, being the primary target of a large number of modern drugs. The availability of structural information of the binding site of the targeted GPCR plays a key role in rationalization, efficiency and cost-effectiveness of the drug discovery process. However, obtaining structural information on GPCRs using X-ray crystallography or NMR requires a large investment of time and is technically very challenging. This situation significantly limits the ability of these methods to have an impact in drug discovery for GPCR targets in the short term and hence there is an urgent need for other effective and cost-efficient alternatives. We present here a practical approach that integrates GPCR modelling with fragment based screening to provide structural insights on the H3 and H4 histamine receptor binding sites. This approach creates a cost-efficient new avenue for structure-based drug design (SBDD) against GPCR targets. We report here a success of using this protocol for the discovery of selective and dual H3 and H4 antagonists. Our fragment screen yielded 44 H3, 21 H4 selective and 20 dual fragment hits. These fragments were used to construct high-quality H3 and H4 models followed by binding site exploration and structure based virtual screening (VS). Overall, 172 compounds were purchased for testing based on the virtual screening results. Of the 74 compounds predicted to have dual activity, 33 had activity against one or other of the two receptors (44%), of which 17 had activity against both. Of the 19 compounds predicted to be H3 selective, 13 were active against H3 (68%) and 10 of these also had selectivity over H4. Of the 79 compounds predicted to be H4 selective, 36 were active against H4 (45%) and 2 of these also had selectivity over H3.

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Identification and hit-to-lead exploration of a novel series of histamine H4 receptor inverse agonists

Cited by 26 publications

References 11 publications

Structure-based virtual screening for fragment-like ligands of the G protein-coupled histamine H₄receptor

Structure-based virtual screening for fragment-like ligands of the G protein-coupled histamine H₄receptor

Antihistamines in Ocular Allergy: Are They All Created Equal?

From Receptors to Ligands: Fragment-assisted Drug Design for GPCRs Applied to the Discovery of H3 and H4 Receptor Antagonists

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Identification and hit-to-lead exploration of a novel series of histamine H4 receptor inverse agonists

Cited by 26 publications

References 11 publications

Structure-based virtual screening for fragment-like ligands of the G protein-coupled histamine H4receptor

Structure-based virtual screening for fragment-like ligands of the G protein-coupled histamine H4receptor

Antihistamines in Ocular Allergy: Are They All Created Equal?

From Receptors to Ligands: Fragment-assisted Drug Design for GPCRs Applied to the Discovery of H3 and H4 Receptor Antagonists

Contact Info

Product

Resources

About

Structure-based virtual screening for fragment-like ligands of the G protein-coupled histamine H₄receptor

Structure-based virtual screening for fragment-like ligands of the G protein-coupled histamine H₄receptor