Evaluation of the cyclopentane-1,2-dione as a potential bio-isostere of the carboxylic acid functional group

Abstract

Cycloalkylpolyones hold promise in drug design as carboxylic acid bio-isosteres. To investigate cyclopentane-1,2-diones as potential surrogates of the carboxylic acid functional group, the acidity, tautomerism, and geometry of hydrogen bonding of representative compounds were evaluated. Prototypic derivatives of the known thromboxane A2 prostanoid (TP) receptor antagonist, 3-(3-(2-((4-chlorophenyl)sulfonamido)-ethyl)phenyl)propanoic acid, in which the carboxylic acid moiety is replaced by the cyclopentane-1,2-dione unit, were synthesized and evaluated as TP receptor antagonists. Cyclopentane-1,2-dione derivative 9 was found to be a potent TP receptor antagonist with an IC50 value comparable to that of the parent carboxylic acid. These results indicate that the cyclopentane-1,2-dione may be a potentially useful carboxylic acid bio-isostere.

Routes to Drug Design Via Bioisosterism of Carboxyl and Sulfonamide Groups

“…Bioisosterism is the replacement of functional groups in a drug molecule while keeping similar biological properties [1,2]. Bioisosteres are useful to enhance the physiochemical [3][4][5][6][7][8][9], pharmacological [10][11][12][13][14][15][16] and pharmacodynamics/pharmacokinetic properties of drugs [17][18][19][20][21][22][23][24][25][26]. For example, tetrazole has been studied as a bioisostere of carboxylic acid in the treatment of the neurodegenerative Alzheimer's disease [3,5].…”

Carboxylic Acid Bioisosteres in Medicinal Chemistry: Synthesis and Properties

“…e thiazolidinedione ring is hypothesized to undergo an oxidative ring-opening reaction by cytochrome P450 that results in the formation of electrophilic metabolites [3,29]. Squaric acids and their derivatives, squaramides, squaramines, and squarates, have also been successfully employed in some settings as carboxylic acid surrogates but contain a very reactive structure and therefore are usually associated with toxicity, a lack of selectivity, and thus promiscuity towards several targets [30][31][32]. Meanwhile, phosphonic, phosphinic, sulfonic, and sul nic acids are nonplanar and relatively highly acidic, leading to increased hydrophilicity and decreased permeability (Table 1) [33].…”

“…CPD1,3s have similar acidity (pK a = 4-5) to carboxylic acid because of dissociation by the delocalization of π-electrons. Meanwhile, CPD1,2 are not vinylogous acid structures and thus have relatively high pK a values [30,147].…”

Evaluation of Oxetan-3-ol, Thietan-3-ol, and Derivatives Thereof as Bioisosteres of the Carboxylic Acid Functional Group

“…The (bio)-isosteric replacement of the carboxylic acid moiety of biologically active compounds is a common strategy in medicinal chemistry that is frequently employed to improve/modify the pharmacokinetic and/or pharmacodynamic properties of compounds of interest. − Although carboxylic acid isosteres are typically designed to mimic the carboxylic acid functional group, it is often the difference in structure and physicochemical properties of the isosteric replacement relative to the carboxylic acid that is critical to the success of this strategy. For this reason, and in consideration of the fact that the success of any isosteric replacement is typically context dependent, the evaluation and development of alternative surrogate structures that could complement and expand the existing set of bioisosteres continues to be a promising area of research. − …”

“…Given our ongoing interest in the area of carboxylic acid bioisosteres, − ,, we set out to investigate a range of physicochemical properties of the oxetan-3-ol, as well as the thietan-3-ol and the corresponding sulfoxide and sulfone structural units. To enable a more informative and rigorous comparison of the properties of these fragments relative to those of carboxylic acids and other known carboxylic acid bioisosteres, we constructed and evaluated a focused set of derivatives of the phenylpropionic acid ( 1 , Table ), as this carboxylic acid was already employed as a template structure in the synthesis and evaluation of a series of analogues comprising a wide selection of known carboxylic acid surrogates .…”