Identification of novel β-lactams and pyrrolidinone derivatives as selective Histamine-3 receptor (H3R) modulators as possible anti-obesity agents

Ghoshal, Anirban; Kumar, Abdhesh; Yugandhar, Doddapaneni; Sona, Chandan; Kuriakose, Sunu; Nagesh, Kommu; Rashid, Mamunur; Singh, Sandeep K.; Wahajuddin, Muhammad; Yadav, Prem N.; Srivastava, Ajay Kumar

doi:10.1016/j.ejmech.2018.04.020

Cited by 52 publications

(27 citation statements)

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“…Our research group is actively engaged in exploring novel post-Ugi transformations [21][22][23][24][25] and recently, we have been working on base-mediated post-Ugi transformations to access novel bioactive compounds for drug discovery. [26][27][28][29] Encouraged by our findings and related research worldwide, we present an exciting review highlighting the base-mediated post-Ugi transformations by trapping the peptidyl anion. In the last decade, many reviews have highlighted the importance and applicability of the Ugi reaction and its post-transformations (Figure 1).…”

Section: Introductionmentioning

confidence: 88%

“…Further medicinal chemistry exploration of this strategy led to the identification of novel histamine-3-receptor (H3R) ligands of series (�)-50 and (�)-51 as potential leads for obesity management (Scheme 16). [28] (�)-51 a was found to possess the highest activity amongst the synthesized compounds with EC 50 (H3R) = 0.1 nM.…”

Section: Metal-free Base-mediated Post-ugi Transformationsmentioning

confidence: 96%

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Advances in Base‐Mediated Post‐Ugi Transformations via Peptidyl Anion Trapping

et al. 2021

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Advances in base‐mediated post‐Ugi transformations are reported and discussed. The minireview encompasses reports showing the abstraction of an alpha proton adjacent to amide carbonyl in aldehyde‐derived Ugi adducts under basic conditions to perform intramolecular and intermolecular cyclizations. The methodologies have been broadly classified depending on the peptidyl anion trapping under metal‐free, metal‐catalyzed, microwave‐assisted, and external electrophile‐aided reaction conditions. A comprehensive analysis of the methods has been presented, highlighting the importance in synthetic and medicinal chemistry.

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Section: Introductionmentioning

confidence: 88%

Section: Metal-free Base-mediated Post-ugi Transformationsmentioning

confidence: 96%

Advances in Base‐Mediated Post‐Ugi Transformations via Peptidyl Anion Trapping

et al. 2021

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“…Compound 1d is an effective histamine-3-receptor-(H3R) agonist at nanomolar concentrations. Therapeutic potential of H3R agonists for the treatment of myocardial ischemia has been demonstrated. , …”

Section: Introductionmentioning

confidence: 99%

Synthesis of Arylidene-β-lactams via exo-Selective Matsuda-Heck Arylation of Methylene-β-lactams

Riemer

Krüger

et al. 2021

J. Org. Chem.

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exo-Methylene-β-lactams were synthesized in two steps from commercially available 3-bromo-2-(bromomethyl)propionic acid and reacted with arene diazonium salts in a Heck-type arylation in the presence of catalytic amounts of Pd(OAc) 2 under ligand-free conditions. The products, arylidene-βlactams, were obtained in high yields as single isomers. The βhydride elimination step of the Pd-catalyzed coupling reaction proceeds with high exo-regioselectivity and E-stereoselectivity. With aryl iodides, triflates, or bromides, the coupling products were isolated only in low yields, due to extensive decomposition of the starting material at elevated temperatures. This underlines that arene diazonium salts can be superior arylating reagents in Hecktype reactions and yield coupling products in synthetically useful yields and selectivities when conventional conditions fail.

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“…31 Finally, a compound set with 94 examples in four compound families with either a β-lactam or a pyrrolidinone central core without basic amino moiety was published recently and surprisingly included compounds with nanomolar functional H 3 R agonist activities (e.g., compound 10 ). 32 The fungal isolates and the multicomponent reaction product 10 are large and complex molecules, which are difficult to align with known H 3 R pharmacophores or H 3 R binding modes for agonists and antagonists. We therefore started a search for novel high-affinity non-imidazole H 3 R full agonists with simpler structures to generate fundamental knowledge on ligand recognition and signaling of the H 3 R.…”

Section: Introductionmentioning

confidence: 99%

4-(3-Aminoazetidin-1-yl)pyrimidin-2-amines as High-Affinity Non-imidazole Histamine H₃ Receptor Agonists with in Vivo Central Nervous System Activity

et al. 2019

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Despite the high diversity of histamine H3 receptor (H3R) antagonist/inverse agonist structures, partial or full H3R agonists have typically been imidazole derivatives. An in-house screening campaign intriguingly afforded the non-imidazole 4-(3-azetidin-1-yl)pyrimidin-2-amine 11b as a partial H3R agonist. Here, the design, synthesis, and structure–activity relationships of 11b analogues are described. This series yields several non-imidazole full agonists with potencies varying with the alkyl substitution pattern on the basic amine following the in vitro evaluation of H3R agonism using a cyclic adenosine monophosphate response element-luciferase reporter gene assay. The key compound VUF16839 (14d) combines nanomolar on-target activity (pKi = 8.5, pEC50 = 9.5) with weak activity on cytochrome P450 enzymes and good metabolic stability. The proposed H3R binding mode of 14d indicates key interactions similar to those attained by histamine. In vivo evaluation of 14d in a social recognition test in mice revealed an amnesic effect at 5 mg/kg intraperitoneally. The excellent in vitro and in vivo pharmacological profiles and the non-imidazole structure of 14d make it a promising tool compound in H3R research.

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Identification of novel β-lactams and pyrrolidinone derivatives as selective Histamine-3 receptor (H3R) modulators as possible anti-obesity agents

Cited by 52 publications

References 53 publications

Advances in Base‐Mediated Post‐Ugi Transformations via Peptidyl Anion Trapping

Advances in Base‐Mediated Post‐Ugi Transformations via Peptidyl Anion Trapping

Synthesis of Arylidene-β-lactams via exo-Selective Matsuda-Heck Arylation of Methylene-β-lactams

4-(3-Aminoazetidin-1-yl)pyrimidin-2-amines as High-Affinity Non-imidazole Histamine H₃ Receptor Agonists with in Vivo Central Nervous System Activity

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Identification of novel β-lactams and pyrrolidinone derivatives as selective Histamine-3 receptor (H3R) modulators as possible anti-obesity agents

Cited by 52 publications

References 53 publications

Advances in Base‐Mediated Post‐Ugi Transformations via Peptidyl Anion Trapping

Advances in Base‐Mediated Post‐Ugi Transformations via Peptidyl Anion Trapping

Synthesis of Arylidene-β-lactams via exo-Selective Matsuda-Heck Arylation of Methylene-β-lactams

4-(3-Aminoazetidin-1-yl)pyrimidin-2-amines as High-Affinity Non-imidazole Histamine H3 Receptor Agonists with in Vivo Central Nervous System Activity

Contact Info

Product

Resources

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4-(3-Aminoazetidin-1-yl)pyrimidin-2-amines as High-Affinity Non-imidazole Histamine H₃ Receptor Agonists with in Vivo Central Nervous System Activity