hNK2 receptor antagonists. The use of intramolecular hydrogen bonding to increase solubility and membrane permeability

Ettorre, Alessandro; D’Andrea, Piero; Mauro, Sandro; Porcelloni, Marina; Rossi, Cristina; Altamura, Maria Maddalena; Catalioto, Rose Marie; Giuliani, Sandro; Maggi, Carlo Alberto; Fattori, Daniela

doi:10.1016/j.bmcl.2011.01.074

Cited by 29 publications

(23 citation statements)

References 12 publications

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“…94 The introduction of a halogen atom at the ortho-position, designed to interact with the N−H, resulted in improved permeability in both a PAMPA and Caco-2 cell layer assay. Although chloro-substituted analog 193 offered an advantage over the prototype, fluoro derivative 194 was found to be superior.…”

Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

Applications of Fluorine in Medicinal Chemistry

et al. 2015

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The role of fluorine in drug design and development is expanding rapidly as we learn more about the unique properties associated with this unusual element and how to deploy it with greater sophistication. The judicious introduction of fluorine into a molecule can productively influence conformation, pKa, intrinsic potency, membrane permeability, metabolic pathways, and pharmacokinetic properties. In addition, (18)F has been established as a useful positron emitting isotope for use with in vivo imaging technology that potentially has extensive application in drug discovery and development, often limited only by convenient synthetic accessibility to labeled compounds. The wide ranging applications of fluorine in drug design are providing a strong stimulus for the development of new synthetic methodologies that allow more facile access to a wide range of fluorinated compounds. In this review, we provide an update on the effects of the strategic incorporation of fluorine in drug molecules and applications in positron emission tomography.

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Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

Applications of Fluorine in Medicinal Chemistry

et al. 2015

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“…However, as stated above, our main focus lies on studies that provide insight into the application of IMHB to optimize permeability and related physicochemical properties. In 2011, Ettorre and co‐workers described the use of IMHBs to increase solubility and membrane permeability in a series of compounds with hNK2 antagonist properties . The authors transformed the original active but poorly permeable compound 1 (Figure ) into derivatives that could form IMHBs and thus mask the polarity of one of the amide bonds.…”

Section: Case Studiesmentioning

confidence: 99%

Intramolecular hydrogen bonding: An opportunity for improved design in medicinal chemistry

Caron

Kihlberg

2019

Medicinal Research Reviews

112

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Recent literature shows that intramolecular hydrogen bond (IMHB) formation can positively impact upon the triad of permeability, solubility, and potency of drugs and candidates. IMHB modulation can be applied to compounds in any chemical space as a means for discovering drug candidates with both acceptable potency and absorption, distribution, metabolism, and excretion‐Tox profiles. Integrating IMHB formation in design of drugs is, therefore, an exciting and timely challenge for modern medicinal chemistry. In this review, we first provide some background about IMHBs from the medicinal chemist's point of view and highlight some IMHB‐associated misconceptions. Second, we propose a classification of IMHBs for drug discovery purposes, review the most common in silico tactics to include IMHBs in lead optimization and list some experimental physicochemical descriptors, which quantify the propensity of compounds to form IMHBs. By focusing on the compounds size and the number of IMHBs that can potentially be formed, we also outline the major difficulties encountered when designing compounds based on the inclusion of IMHBs. Finally, we discuss recent case studies illustrating the application of IMHB to optimize cell permeability and physicochemical properties of small molecules, cyclic peptides and macrocycles.

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“…Furthermore, the accessibility of polar atoms in a molecule could be decreased if IMHBs are established. This may influence desolvation equilibria and facilitate the passage of molecules through low dielectric environments [216,217,218]. While geometric preferences for the formation of IMHBs have been described based on experimental evidence [67], the presence of stabilizing IMHBs are normally debated based on thermodynamics grounds, especially in high dielectric environments.…”

Section: Intramolecular Hydrogen Bondsmentioning

confidence: 99%

It Is Important to Compute Intramolecular Hydrogen Bonding in Drug Design?

Yunta¹

2017

AJMO

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The effect of weak intermolecular interactions on the binding affinity between ligand-protein complexes plays an important role in stabilizing a ligand at the interface of a protein structure. In this review article, we will explore the different ways of taking into account these interactions, mainly intramolecular hydrogen bonds, in docking calculations. Their possible limitations and their suitable application domains are highlighted. Inspection of the outliers of this study probed very stimulating, as it provides opportunities and inspiration to medicinal chemists, being a reminder of the impact that minimal chemical modifications can have on biological activities.

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hNK2 receptor antagonists. The use of intramolecular hydrogen bonding to increase solubility and membrane permeability

Cited by 29 publications

References 12 publications

Applications of Fluorine in Medicinal Chemistry

Applications of Fluorine in Medicinal Chemistry

Intramolecular hydrogen bonding: An opportunity for improved design in medicinal chemistry

It Is Important to Compute Intramolecular Hydrogen Bonding in Drug Design?

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