Determination of the active conformation of 6-amino-α-[(4-diphenylmethyl-1-piperazinyl)methyl-9H-purine]-9-ethanol: a positive inotropic agent

Miltz, Wolfgang; Zierhurt, Wolfgang; Buccheri, Elena; Schultz, R. J.; Stirnimann, Roger

doi:10.1016/s0960-894x(00)80322-4

Cited by 5 publications

(5 citation statements)

References 11 publications

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“…6-(2-Thienyl)-IH-purine (14). Method D. This procedure illustrates the general method for preparation of 12-14 using the appropriate Grignard reagent and either 3143 or 3213 as the starting materials.…”

Section: Methodsmentioning

confidence: 99%

“…The most prevalent is DPI 210-106 (l),6 which has undergone extensive preclinical evaluation as an inotrope,7 an antiarrhythmic,8 and a vasodilator9 and has been evaluated in humans for the treatment of congestive heart failure.10 Other structurally related compounds which have been shown to delay the inactivation of cardiac Na channels include the cyanoindoles SDZ 210-921 (2)11 and BDF 9148 (3), 12 as well as a series of 6-thiopurines exemplified by carsatrin (4)13 and the adenine-based SDZ 211-500 (5). 14 We were intrigued by the diversity of heterocyclic moieties to which the common (hydroxypropyl)benzhydrylpiperazine chain was attached and sought to explore the specific structural requirements within the series 1-5. At the same time, we hoped to probe the roles of the benzhydrylpiperazine (BHP) unit and connecting chain, with the goal of optimizing the activity at the Na channel site while minimizing potential ancillary receptor interactions anticipated by the presence of two pharmacologically prolific fragments.…”

Section: Introductionmentioning

confidence: 99%

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Synthesis and Structure-Activity Relationships of 6-Heterocyclic-Substituted Purines as Inactivation Modifiers of Cardiac Sodium Channels

Estep¹,

Josef²,

Bacon³

et al. 1995

J. Med. Chem.

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Purine-based analogs of SDZ 211-500 (5) were prepared and evaluated as inactivation modifiers of guinea pig or human cardiac sodium (Na) channels expressed in Xenopus oocytes. Substances which remove or slow the Na channel inactivation process in cardiac tissue are anticipated to prolong the effective refractory period and increase inotropy and thus have potential utility as antiarrhythmic agents. Heterocyclic substitution at the 6-position of the purine ring resulted in compounds with increased Na activity and potency, with 5-membered heterocycles being optimal. Only minor modifications to the benzhydrylpiperazine side chain were tolerated. Selected compounds which delayed the inactivation of Na channels were found to increase refractoriness and contractility in a rabbit Langendorff heart model, consistent with the cellular mechanism. Activity in both the oocyte and rabbit heart assays was specific to the S enantiomers. Preliminary in vivo activity has been demonstrated following intravenous infusion. The most promising compound on the basis of in vitro data is the formylpyrrole (S)-74, which is 25-fold more potent than DPI 201-106 (1) in the human heart Na channel assay.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Synthesis and Structure-Activity Relationships of 6-Heterocyclic-Substituted Purines as Inactivation Modifiers of Cardiac Sodium Channels

Estep¹,

Josef²,

Bacon³

et al. 1995

J. Med. Chem.

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“…It enhances the contractile force of the rat's and rabbit's hearts similar to DPI 201‐106 by a mechanism involving fast Na + channels. [ 86 ]…”

Section: Ion Channel Blockersmentioning

confidence: 99%

“…It enhances the contractile force of the rat's and rabbit's hearts similar to DPI 201-106 by a mechanism involving fast Na + channels. [86] Subsequently, the (-)-(S)-isomer of this compound was subjected to a more detailed study, which received the code SDZ 211-939. In Langendorff-perfused hearts from rats and rabbits, SDZ 211-939 at concentrations between 10 −8 and 10 −6 M increased force of contraction, increased (rabbit) or decreased HR and prolonged repolarisation in the electrocardiogram (ECG) (rat).…”

Section: Purine Derivativesmentioning

confidence: 99%

“…In 2002, researchers from Icagen Inc. and Eli Lilly and Company (USA) patented the thiazolidinone derivatives 41 as Kv1.5 blockers (Figure 30). Compounds inhibited the 86 Rb efflux through Kv1.5 potassium channels expressed in CHO cells. These results were also confirmed using the whole-cell configuration of the patch-clamp technique.…”

Section: Ortho-disubstituted Bisaryl Compoundsmentioning

confidence: 99%

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Linked biaromatic compounds as cardioprotective agents

Mokrov

2021

Archiv der Pharmazie

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Cardiovascular diseases (CVDs) are widespread in the modern world, and their number is constantly growing. For a long time, CVDs have been the leading cause of morbidity and mortality worldwide. Drugs for the treatment of CVD have been developed almost since the beginning of the 20th century, and a large number of effective cardioprotective agents of various classes have been created. Nevertheless, the need for the design and development of new safe drugs for the treatment of CVD remains. Literature data indicate that a huge number of cardioprotective agents of various generations and mechanisms correspond to a single generalized pharmacophore model containing two aromatic nuclei linked by a linear linker. In this regard, we put forward a concept for the design of a new generation of cardioprotective agents with a multitarget mechanism of action within the indicated pharmacophore model. This review is devoted to a generalization of the currently known compounds with cardioprotective properties and corresponding to the pharmacophore model of biaromatic compounds linked by a linear linker. Particular attention is paid to the history of the creation of these drugs, approaches to their design, and analysis of the structure-action relationship within each class.

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Reductive Aminations of Carbonyl Compounds with Borohydride and Borane Reducing Agents

2002

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Reductive amination is an important tool for synthetic organic chemists in the construction of carbon‐nitrogen bonds. This reaction, also termed reductive alkylation, involves condensation of an aldehyde or ketone with an amine in the presence of a reducing agent. A wide variety of substrates can be used including aliphatic and aromatic aldehydes and ketones, and even benzophenones. A range of amines from ammonia to aromatic amines, including those with electron‐withdrawing substituents, can be employed. For particularly sluggish reactions, such as those involving weakly electrophilic carbonyl groups, poorly nucleophilic amines, or sterically congested reactive centers, additives such as molecular sieves or Lewis acids are often useful. This chapter focuses on those conditions in which the carbonyl component, amine, and reducing reagent react in the same vessel. This review is restricted to reductive aminations using borohydride and borane reducing agents. This chapter concentrates on reductive amination chemistry mediated by borohydride and other boron‐containing reducing agents from 1971, the year when sodium cyanoborohydride was introduced, through the middle of 1999. In addition to reductive aminations of aldehyde and ketone substrates, reactions of related structures including acetals, aminals, ketals, carboxylic acids, nitriles, and dicarbonyls that form a nitrogen‐containing ring are reviewed. Intramolecular processes in which the substrate contains both the carbonyl and amine moieties are described. The intramolecular variant is a useful method for preparing cyclic amines. All of the various boron‐containing hydride sources in reductive aminations, including labeled metal hydrides, are reviewed. Instances of reductive aminations that failed are described. Applications of this method to a solid support in parallel synthesis in combinatorial chemistry as well as reductive aminations that proceed in tandem with a second reaction such as reductive lactamizations are discussed.

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Determination of the active conformation of 6-amino-α-[(4-diphenylmethyl-1-piperazinyl)methyl-9H-purine]-9-ethanol: a positive inotropic agent

Cited by 5 publications

References 11 publications

Synthesis and Structure-Activity Relationships of 6-Heterocyclic-Substituted Purines as Inactivation Modifiers of Cardiac Sodium Channels

Synthesis and Structure-Activity Relationships of 6-Heterocyclic-Substituted Purines as Inactivation Modifiers of Cardiac Sodium Channels

Linked biaromatic compounds as cardioprotective agents

Reductive Aminations of Carbonyl Compounds with Borohydride and Borane Reducing Agents

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