Pyridobenzodiazepines: A novel class of orally active, vasopressin V2 receptor selective agonists

Failli, Amedeo; Shumsky, Jay S.; Steffan, Robert J.; Caggiano, Thomas J.; Williams, David; Trybulski, Eugene J.; Ning, Xiaoping; Lock, Yeung-Wai; Tanikella, T.; Hartmann, David J.; Chan, Peter S.; Park, C.H.

doi:10.1016/j.bmcl.2005.10.107

Cited by 42 publications

(16 citation statements)

References 20 publications

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“…As a general class, benzodiazepines have enjoyed remarkable success as a privileged scaffold in the construction of pharmacologically active substances that improve human health. , The subsets of dihydropyridobenzodiazepines have received less attention historically; however, they recently have generated interest as inhibitors of IDH mutant enzymes and as potential agonists for bombesin receptor subtype-3 or vasopressin V2 receptors …”

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confidence: 99%

“…Most existing routes to functionalized dihydropyridobenzodiazepines involve condensation of a 2-halo-nicotinic acid derivative with a dianiline followed by lactam reduction and subsequent derivatization of the heterocyclic scaffold (Scheme , top). , While concise, this approach has suffered from a number of drawbacks, for instance, control of regiochemistry, moderate yields associated with lactam reduction, generally poor organic solubility, associated challenges with purification, and finally, potential regiochemical issues related to selective functionalization at either nitrogen of the central diazepine. In an effort to develop a general method that effectively addresses all of the challenges mentioned above, we have explored a C–N coupling/reductive cascade approach to access the desired dihydropyridobenzodiazepines.…”

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confidence: 99%

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Metal Catalyzed Synthesis of Dihydropyridobenzodiazepines

Maddess

2018

Organometallics

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confidence: 99%

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Metal Catalyzed Synthesis of Dihydropyridobenzodiazepines

Maddess

2018

Organometallics

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“…Despite a high sequence similarity between OT and vasopressin;8 OTR and vasopressin receptors (V1AR, V1BR, V2R)9 and the availability of non‐peptide vasopressin receptor agonists,10,11 identifying OTR non‐peptide agonists has proven to be extremely difficult. We notably showed that systematic variations of known V1AR and V2R agonists only lead to OTR antagonists but not to agonists 12.…”

Section: Functional Antagonist Effect Of 10 Hitsmentioning

confidence: 99%

Identification of Nonpeptide Oxytocin Receptor Ligands by Receptor‐Ligand Fingerprint Similarity Search

Weill

Valencia

Gioria

et al. 2011

Molecular Informatics

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Oxytocin (OT) is a peptide hormone secreted by the pituitary gland that binds to a specific G protein-coupled receptor (OTR) to mediate both peripheral and central actions.[1] It notably induces uterine contraction during labor and stimulates lactation in breast-feeding mothers. Centrally, OT is implicated in numerous social behaviors [2][3][4] including pair bonding, maternal behavior, sexual arousal, learning, selfconfidence and is often referred as the hormone of love. [5] As most peptides, OT displays very poor pharmacokinetic properties and does not cross the blood-brain barrier [6] . Non-peptide orally-available and selective OTR agonists would be of invaluable help to better investigate the still poorly known central effects of OT and enable the treatment of pathologies (e.g. male erectile dysfunction) where OT function is impaired. Only one OTR partial agonist (compound 1, Figure 1), discovered from a gene reporter highthroughput screen [7] is known to date.Despite a high sequence similarity between OT and vasopressin; [8] OTR and vasopressin receptors (V1AR, V1BR, V2R) [9] and the availability of non-peptide vasopressin receptor agonists, [10,11] identifying OTR non-peptide agonists has proven to be extremely difficult. We notably showed that systematic variations of known V1AR and V2R agonists only lead to OTR antagonists but not to agonists.[12] Likewise, truncation of the terminal homopiperazine ring leads to a functional antagonist (compound 2, Figure 1), illustrating very subtle structure-activity relationships. [12] As part as our global initiative for identifying novel nonpeptide OTR agonists, we herewith report the in silico screening of an in-house collection of commercially-available drug-like compounds (Bioinfo-DB).[13] Since the X-ray structure of OTR is currently unavailable and docking-based screening of GPCR ligands require preliminary knowledge (known ligands, site-directed mutagenesis data) [14] that were missing, we restricted the panel of possible approaches to ligand-centric methods. Three similarity search methods (topomer matching, [15] shape overlap, [16] circular fingerprint similarity [17] ) were applied to find 91 hits similar to reference compound 1. In addition, a recently described chemogenomic screening method (PLFP) based on concatenated protein-ligand fingerprints [18] was utilized. Chemogenomic [19] (or proteochemometric [20] ) methods circumvent known limitations of pure ligand-based quantitative structure-activity (QSAR) approaches by considering both ligand and target descriptors [20][21][22] to predict target-ligand associations (binding affinities, [23,24] complex formation [18] ). Since similar receptors are supposed to bind to similar ligands, [25] novel interactions can thus be inferred from known data on similar ligands and/or similar targets. In the current study, PLFP screening provided 37 additional virtual hits.The above described 128 compounds were tested in duplicate at two concentrations (1 and 10 mM) in a functional fluorescence-based assay on HEK cells o...

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“…Moreover, as clozapine-like analogs, 8-chloro-6-(4 0 -methyl-l-piperazinyl)-11H-pyrido [2,3-b] [1,4] benzodiazepine (4) and 8-methyl-6-(4 0 -methyl-1-piperaziny1)-11H-pyrido [2,3-b] [1,4] benzodiazepine (5) showed the behavioral features for neuroleptics [10,11]. Pyridobenzodizepine derivatives have been extensively studied as potential agents to modulate activities of the central nervous system and vasopressin V 2 receptor [12,13].…”

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A rapid synthetic method of pyridobenzodiazepines

et al. 2010

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A new one-pot Bischler-Napeiralski type cyclization reaction between pyridine-1,2-diamines and various carboxylic acids with PPA as catalyst to prepare pyridobenzodiazepines is proposed. In the new synthetic route, the reaction time is only one-third of the methods reported. The synthetic strategy provides an efficient way to prepare novel structurally diversified heterocyclic compounds of pyridobenzodiazepine family with potential pharmaceutical or biological activities.

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Pyridobenzodiazepines: A novel class of orally active, vasopressin V2 receptor selective agonists

Cited by 42 publications

References 20 publications

Metal Catalyzed Synthesis of Dihydropyridobenzodiazepines

Metal Catalyzed Synthesis of Dihydropyridobenzodiazepines

Identification of Nonpeptide Oxytocin Receptor Ligands by Receptor‐Ligand Fingerprint Similarity Search

A rapid synthetic method of pyridobenzodiazepines

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