Substituted phenoxypropyl-(R)-2-methylpyrrolidine aminomethyl ketones as histamine-3 receptor inverse agonists

Zulli, Allison L.; Aimone, Lisa D.; Mathiasen, Joanne R.; Gruner, John A.; Raddatz, Rita; Bacon, Edward R.; Hudkins, Robert L.

doi:10.1016/j.bmcl.2012.02.081

Cited by 10 publications

(2 citation statements)

References 23 publications

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“…The 4,4-difluoropiperidine moiety of 512 was an effective replacement for the morpholine heterocycle in 511 in a series of histamine-3 receptor inverse agonists, with both compounds exhibiting comparable affinity for the human receptor . The prototype 511 was also a potent rat H 3 receptor ligand that exhibited high selectivity over the hERG channel (21% inhibition at 10 μM) and CYP inhibition (IC 50 > 30 μM) while presenting good metabolic stability in mouse, rat, dog, monkey, and human LMs ( t 1/2 > 40 min), high Caco-2 cell permeability, and low plasma protein binding.…”

Section: Cf2 As a Bioisostere Of An Oxygen Atommentioning

confidence: 99%

Fluorine and Fluorinated Motifs in the Design and Application of Bioisosteres for Drug Design

2018

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The electronic properties and relatively small size of fluorine endow it with considerable versatility as a bioisostere and it has found application as a substitute for lone pairs of electrons, the hydrogen atom, and the methyl group while also acting as a functional mimetic of the carbonyl, carbinol, and nitrile moieties. In this context, fluorine substitution can influence the potency, conformation, metabolism, membrane permeability, and P-gp recognition of a molecule and temper inhibition of the hERG channel by basic amines. However, as a consequence of the unique properties of fluorine, it features prominently in the design of higher order structural metaphors that are more esoteric in their conception and which reflect a more sophisticated molecular construction that broadens biological mimesis. In this Perspective, applications of fluorine in the construction of bioisosteric elements designed to enhance the in vitro and in vivo properties of a molecule are summarized.

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Section: Cf2 As a Bioisostere Of An Oxygen Atommentioning

confidence: 99%

Fluorine and Fluorinated Motifs in the Design and Application of Bioisosteres for Drug Design

2018

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“…The generally acceptable and widely used method to prepare monosubstituted piperazines is based on the employment of protecting groups such as tert-butyloxycarbonyl (Boc) or similar alkoxycarbonyl, acyl or benzyl groups [34][35][36][37]. The main disadvantage of such approach is the multi-step synthetic procedure.…”

Section: Introductionmentioning

confidence: 99%

Simplified Procedure for General Synthesis of Monosubstituted Piperazines—From a Batch Reaction Vessel to a Flow (Microwave) Reactor

et al. 2020

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We reported a novel simplified synthetic procedure for the preparation of monosubstituted piperazine derivatives which can now be easily prepared in a one-pot-one-step way from a protonated piperazine with no need of introduction of a protecting group. Reactions, proceeding either at room or higher temperatures in common solvents, involve heterogeneous catalysis by metal ions supported on commercial polymeric resins. A general synthetic scheme was successfully applied to afford a wide range of monosubstituted piperazines. Furthermore, we picked up a set of piperazine derivatives and studied the possibilities of microwave acceleration of given synthetic reactions to make them even more efficient. Our research proceeded from a simple batch technique to the construction of a flow microwave reactor prototype and resulted in promising findings which are summarized and discussed in the article.

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Nitrogen Heterocycle Synthesis through Hydride Abstraction of Acyclic Carbamates and Related Species: Scope, Mechanism, Stereoselectivity, and Product Conformation Studies

Miller,

Damodaran,

Floreancig

2023

Chemistry A European J

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Acyliminium ions and related species are potent electrophiles that can be quite valuable in the synthesis of nitrogen‐containing molecules. This manuscript describes a protocol to form these intermediates through hydride abstractions of easily accessible allylic carbamates, amides, and sulfonamides that avoids the reversibility that is possible in classical condensation‐based routes. These intermediates are used in the preparation of a range of nitrogen‐containing heterocycles, and in many cases high levels of sterocontrol are observed. Specifically areas of investigation include the impact of chemical structure on oxidation efficiency, the geometry of the intermediate iminium ions, the impact of a substrate stereocenter on stereocontrol, and an examination of transition state geometry.

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Substituted phenoxypropyl-(R)-2-methylpyrrolidine aminomethyl ketones as histamine-3 receptor inverse agonists

Cited by 10 publications

References 23 publications

Fluorine and Fluorinated Motifs in the Design and Application of Bioisosteres for Drug Design

Fluorine and Fluorinated Motifs in the Design and Application of Bioisosteres for Drug Design

Simplified Procedure for General Synthesis of Monosubstituted Piperazines—From a Batch Reaction Vessel to a Flow (Microwave) Reactor

Nitrogen Heterocycle Synthesis through Hydride Abstraction of Acyclic Carbamates and Related Species: Scope, Mechanism, Stereoselectivity, and Product Conformation Studies

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