Non-imidazole heterocyclic histamine H3 receptor antagonists

Chai, Wenying; Breitenbucher, J. Guy; Kwok, Annette; Li, Xiaobing; Wong, Victoria; Carruthers, Nicholas I.; Lovenberg, Timothy W.; Mazur, Curt; Wilson, Sandy J.; Axe, Frank U.; Jones, Todd K.

doi:10.1016/s0960-894x(03)00299-3

Cited by 104 publications

(40 citation statements)

References 19 publications

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“…Several groups have reported the discovery of potent and selective non-imidazole H 3 receptor antagonists [16][17][18][19][20]. In general these compounds differ from H 1 , H 2 and even H 4 receptor antagonists in their chemical structures and features, and the general H 3 pharmacophore has been described [17].…”

Section: Introductionmentioning

confidence: 99%

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Three-dimensional models of histamine H3 receptor antagonist complexes and their pharmacophore

Axe¹,

Bembenek

Szalma³

2006

Journal of Molecular Graphics and Modelling

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Section: Introductionmentioning

confidence: 99%

“…And these two basic centers are linked by a lipophilic group [17]. Several examples of H 3 antagonists illustrating the features of this pharmacophore [16][17][18] are shown in Fig. 1.…”

Section: Introductionmentioning

confidence: 99%

Three-dimensional models of histamine H3 receptor antagonist complexes and their pharmacophore

Axe¹,

Bembenek

Szalma³

2006

Journal of Molecular Graphics and Modelling

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“…The molecules were from diverse classes: 5-arylaminobenzofuran [19], aliphatic ether [20], cinnamic amides [21], urea analogs of cinnamic amides [22], 4-(aminoalkoxy)benzylamines [8], imidazopyridines [23], 4-phenoxypiperidine [24], indazoline [25], omega-piperidinoalkalamine [26], d-amino acid homopiperazineamides [27], azepine [28], quinoline [29], and benzimidazolones [30].…”

Section: Biological Datamentioning

confidence: 99%

Pharmacophore Refinement and 3D‐QSAR Studies of Histamine H₃ Antagonists

Narkhede

Degani

2007

QSAR Comb. Sci.

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Molecular modeling studies were performed to develop a predictive Common Pharmacophore Hypothesis (CPH) and use it for alignment in 3D-QSAR studies using CoMFA and CoMSIA, with a diverse set of 106 histamine H 3 antagonists. A five point CPH with three hydrophobic features, a basic or positive ionizable feature and an acceptor, for pharmacophore-based alignment of molecules, was derived using PHASE. This hypothesis was selected from a pool, by correlating the observed and estimated activity for the training set and test set of molecules using partial least square analysis. It was found to be comparable to the previously reported hypothesis. The validated pharmacophore hypothesis was used for alignment of molecules in CoMFA and CoMSIA model development. The models so generated showed a good "predictive" r 2 value of 0.763 and 0.820 for CoMFA and CoMSIA, respectively. The contour maps of the models were analyzed to give structural insight for activity improvement of future novel histamine H 3 antagonists. The CPH can also provide a powerful template for virtual screening and design of new histamine H 3 antagonists.

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“…17a This prompted us to investigate the feasibility of this methodology in the synthesis of indoles of potential pharmacological interest. 5,18 Herein, we report a straightforward and one-pot Pd/C-catalyzed synthesis of 2-substituted indoles in water.…”

Section: Scheme 1 Palladium-catalyzed Synthesis Of Indolesmentioning

confidence: 99%

Synthesis of 2-Substituted Indoles via Pd/C-Catalyzed Reaction in Water

Pal¹,

Subramanian²,

Batchu³

et al. 2004

Synlett

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A general and one-pot synthesis of 2-alkyl/aryl substituted indoles via a tandem Pd/C mediated coupling/5-endo-dig cyclization of terminal alkynes (including acetylenic carbinols) with o-iodoanilides in water is reported. The reaction is carried out using PPh 3 and CuI as co-catalysts and 2-aminoethanol as a base. The reaction appears to tolerate a variety of functional groups present in the alkynes and does not require the use of any organic co-solvent.The indole nucleus is a frequently found unit in many natural products and diverse biologically active molecules. 2 Interesting pharmacological properties, such as antithrombotic, 3 anticancer, 4 histamine H 3 receptor antagonism 5 etc. exhibited by the various 2-substituted indoles have led to a continued interest in the practical synthesis of these compounds. Among the classical methods for the synthesis of indole ring, the Fischer indole synthesis, the Batcho-Leimgruber synthesis (from o-nitrotoluenes and dimethylformamide acetals), the Gassman synthesis (from N-haloanilines), the reductive cyclization of o-nitrobenzylketones and the Madelung cyclization of N-acyl-o-toluidines are often used. However, the introduction of an aryl group at the 2-position of an indole ring is usually achieved by de novo indole ring construction 6 either by Fischer indole synthesis or more popularly by transition metal mediated reactions, 7 especially by palladium catalyzed protocols. 8-10 Palladium-catalyzed annulation of o-haloanilines with terminal alkynes (under Sonogashira reaction conditions) or internal alkynes (under Larock's conditions) has been employed widely due to the versatile nature of these protocols, increased functional group tolerance and improved yields (Scheme 1). Despite being quite versatile, the synthesis of 2-substituted indoles employing terminal alkynes often involves a twostep process i.e. Sonogashira coupling of o-haloanilines with terminal alkynes followed by the cyclization of the resulting 2-alkynylanilines in the presence of various reagents (e.g. metal alkoxides, halides or Lewis acids). 11 Moreover, cyclization of anilides having an alkynol moiety at the 2-position yielded quinolines/2,3-dihydro-4(1H)-quinolones rather than indoles. 11d Very recently, a one-pot synthesis of 2-substituted indoles has been reported in the presence of Pd(II)-NaY zeolite catalysts. 8a However, the reaction was carried out in a sealed tube and appeared to be unsuitable for the preparation of these compounds in a large scale. Scheme 1 Palladium-catalyzed synthesis of indolesPalladium-promoted reactions in aqueous media are a focus of current research 12,13 because water-based synthetic processes are inherently safer as well as inexpensive (especially for industrial-scale processes). Therefore, the use of water-soluble catalysts 13g and water-soluble phosphine ligands 13f has been explored successfully. The use of Pd/ C-CuI-PPh 3 as a catalyst system for efficient Sonogashira coupling has also been reported. 14,15 All these Pdcatalyzed reactions are usually carried out i...

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Non-imidazole heterocyclic histamine H3 receptor antagonists

Cited by 104 publications

References 19 publications

Three-dimensional models of histamine H3 receptor antagonist complexes and their pharmacophore

Three-dimensional models of histamine H3 receptor antagonist complexes and their pharmacophore

Pharmacophore Refinement and 3D‐QSAR Studies of Histamine H₃ Antagonists

Synthesis of 2-Substituted Indoles via Pd/C-Catalyzed Reaction in Water

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Non-imidazole heterocyclic histamine H3 receptor antagonists

Cited by 104 publications

References 19 publications

Three-dimensional models of histamine H3 receptor antagonist complexes and their pharmacophore

Three-dimensional models of histamine H3 receptor antagonist complexes and their pharmacophore

Pharmacophore Refinement and 3D‐QSAR Studies of Histamine H3 Antagonists

Synthesis of 2-Substituted Indoles via Pd/C-Catalyzed Reaction in Water

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Pharmacophore Refinement and 3D‐QSAR Studies of Histamine H₃ Antagonists