Cycloalkyl-dione derivatives with improved pharmacokinetic and toxicological properties for drug design
Isosteric replacement of a specific group of atoms with a moiety with similar physicochemical properties is a strategy employed by medicinal chemists to improve the properties of biologically active compounds. For example, carboxylic acid isosteres are used to substitute the carboxylic acid moiety in pharmaceutical compounds to improve potency, selectivity, stability, and pharmacokinetics, while retaining the functionality of the carboxylic acid. Carboxylic acids are a common functional group in small molecules that bind to protein targets. However, these moieties can be detrimental in pharmaceuticals because of limited permeability across biological membranes, toxicity, and metabolic instability, although the water solubility and acidity conferred are beneficial for facilitating electrostatic interactions with the biological target. A facile method to predict the outcome of an isosteric replacement does not exist.
Because cyclopentane-1,3-dione has a pKa value comparable to carboxylic acids, the researchers explored this unit as a carboxylic acid isostere and its use in drug design. Derivatives of a known thromboxane A2 prostanoid receptor antagonist were synthesized, and the biological activity was comparable to the parent compound as determined by functional and radioligand-binding assays.
Structure of known thromboxane receptor antagonist 12 (top) and overlap of the carboxylic acid moiety of (12) with cyclopentane-1,3-dione (CPD) derivatives attached at either C2 or C4/C5 (bottom, A or B, respectively). From Ballatore et al, 2011
- Improved pharmacokinetic, toxicological, and safety profiles
- Modulate drug target/off-target interactions
- Tunable lipophilicity, acidity, and other chemical properties of biologically active compounds
- Compounds able to cross blood/brain barrier
Compounds with carboxylic acid moieties, including pharmaceuticals, polymers, solvents, food additives
Stage of Development:
In vitro proof-of-concept
- Lassalas P. et al. J. Med. Chem., 2016, 59, p. 3183-3203.
- Ballatore C. et al. Bioorg. Med. Chem. Lett., 2014, 24, p. 4175-4177.
- Ballatore C. et al. Chem. Med. Chem., 2013, 8, p. 385-395.
- Ballatore C. et al. J. Med. Chem., 2011, 54, p. 6969-6983.
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