Although the overall profile of was encouraging we pursued i
Although the overall profile of was encouraging, we pursued its optimization based on SAR studies imported from a novel class of compounds in which the sulfonamide moiety of MK-7246 was replaced by an amide group. Potential liabilities related to the presence of a sulfonamides group (i.e., allergic reaction to ‘sulfa’ drugs) as well as the potential for in vivo covalent binding found for Deoxynivalenol MK-7246 and () were the main drivers for exploring this new chemical space.
Following the sequence shown in , we converted the previously obtained sulfonamide intermediate into amides via a magnesium radical reduction of the sulfonamide to the secondary amine. The resulting amine was diversified using a series of different carboxylic acids using HATU coupling conditions followed by hydrolysis under standard conditions to obtain antagonists –.
Most amides obtained through this process showed low nanomolar activity on both the binding and the whole blood assays (). They also showed excellent selectivity for the CRTH2 receptor over the other prostanoid receptors. Pharmacokinetic studies in rats on this class of compounds revealed that they were orally bioavailable and exhibited a wide range of clearance rates and half-lives ().
From these studies, two compounds (, ) stood out for their low clearance and relatively high bioavailability, although, these results are based on only two animals. The improved CYP profile (i.e., lower CYP2C9 inhibition) observed with translated equally well in the amide series as shown by the similar results obtained for compound (). In addition, was found to display a lower activation constant (), a hallmark measurement of CYP3A4 time dependant inhibition (TDI) and a significantly lower in vivo covalent binding as compared to MK-7246 (). A reduced TDI of CYP3A4 for compound lowers the risks of potential drug–drug interaction caused by gradual accumulation of irreversible or quasi irreversible binders to the cytochrome active site.
In conclusion, the indole core found in MK-7246 was effectively replaced by a 7-azaindole core while retaining affinity for the CRTH2 receptor and activity in the eosinophil shape change whole blood assay. The selectivity over other prostanoid receptors, mainly DP and TP, was improved as well as the CYP profile. The introduction of an amide group in lieu of the sulfonamide moiety reduced the shift in the EOS whole blood assay but more importantly solved the covalent binding issue that was observed with our lead compound. As a result of the SAR studies described in this manuscript, we identified the azaindole as a potential backup compound that addressed the potential liabilities associated with MK-7246.
Prostaglandin D (PGD) plays a key role in mediating allergic reactions such as those seen in asthma, allergic rhinitis, atopic dermatitis and allergic conjunctivitis. PGD is the major cyclooxygenase product formed and secreted by activated mast cells and its levels in bronchoalveolar lavage (BAL) fluid increase in response to antigen provocation., , , , In animals, including humans, PGD stimulates several responses observed in asthma and other immune diseases such as airway constriction, mucus secretion, increased microvascular permeability and recruitment of eosinophils., , , , , In addition, mice that overexpress PGD synthase, resulting in overproduction of PGD, experience increased levels of Th2 cytokines and chemokines accompanied by enhanced accumulation of eosinophils and lymphocytes in the lung following an allergic response to ovalbumin. Thus, PGD is thought to be involved in the acute and late phases of allergic reactions. PGD activates two receptors, DP (prostanoid D receptor, DP) and CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells, DP).