| Autor: |
Möbitz H; Novartis BioMedical Research, 4002 Basel, Switzerland., Dittrich B; Novartis BioMedical Research, 4002 Basel, Switzerland., Rodde S; Novartis BioMedical Research, 4002 Basel, Switzerland., Strang R; Novartis BioMedical Research, 4002 Basel, Switzerland. |
| Jazyk: |
angličtina |
| Zdroj: |
Journal of medicinal chemistry [J Med Chem] 2024 Jun 13; Vol. 67 (11), pp. 9485-9494. Date of Electronic Publication: 2024 May 15. |
| DOI: |
10.1021/acs.jmedchem.4c00596 |
| Abstrakt: |
The ionization of bioactive molecules impacts many ADME-relevant physicochemical properties, in particular, solubility, lipophilicity, and permeability. Ampholytes contain both acidic and basic groups and are distinguished as ordinary ampholytes and zwitterions. An influential review states that zwitterions only exist if the acidic p K a is significantly lower than the basic p K a . Through concordance of measured and calculated p K a and log P , we show that the zwitterionic behavior of several marketed drugs and natural products occurs despite a low or negative Δp K a . These nonclassical zwitterions are characterized by a weak acidic and basic p K a and conjugation through an extended aromatic system, often including pseudorings via intramolecular hydrogen bonds. In contrast to most classical zwitterions, nonclassical zwitterions can exhibit excellent permeability. As permeability and lipophilicity are typically correlated, the combination of low lipophilicity and high permeability makes nonclassical zwitterions an attractive design principle in medicinal chemistry. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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