2.B.81. The Diaxial Diureido Decalin (DDD) Family
Diaxial Diureido Decalins are compact, efficient, and tunable anion transporters (Hussain et al. 2011). Decalins bearing two axial -NHCONHAr substituents and an ester-linked alkyl side chain have been synthesized and studied as anion receptors and transporters. The design relates to steroid-based 'cholapods' but is more compact and less intrinsically lipophilic. Transport rates depend on both NHAr and the alkyl side chain. High activities can be achieved; with optimal substitution, chloride-nitrate exchange across vesicle membranes is measurable at transporter/lipid ratios as low as 1:250,000 (Hussain et al. 2011).
Current therapeutic options for cystic fibrosis (CF) include pharmacological modulation of the protein using the so-called potentiators and correctors. The outcomes of these treatments dramatically depend on the type of mutation carried by the patient, and the best results were obtained by using a combination of these molecules such as the recently approved triple combination therapy Trikafta™ (elexacaftor/ivacaftor/tezacaftor). Thus, exploring the potential synergy or additivity of anionophores with approved FDA CFTR drugs is an important goal. In two independent studies, the additivity of the action of active anionophores to CFTR potentiators was demonstrated for two different classes of compounds, suggesting that this might be a general trend for the action of anionophores (Fiore et al. 2019). Davis et al. 2020 reported on an exploration of a library of active anionophores based on scaffolds bearing (thio)urea groups and demonstrated that decalin-based 11b (see figure below) offered promise as a future CF drug candidate because of its transport activity in YFP-modified CF airway epithelial cells (Li et al. 2019). This compound showed additivity with the activity of CFTR potentiator ivacaftor and CF corrector lumacaftor, which are used in the clinic. An important concern is the toxicity of the induced anion transport.