Selective Optimization of Pranlukast to Farnesoid X Receptor Modulators

Abstract

Selective optimization of side activities (SOSA) offers an alternative entry to early drug discovery and may provide rapid access to bioactive new chemical entities with desirable properties. SOSA aims to reverse a drug's side activities through structural modification and to design out the drug's original main action. We identified a moderate side activity for the cysteinyl leukotriene receptor 1 (CysLT1R) antagonist pranlukast on the farnesoid X receptor (FXR). Systematic structural modification of the drug allowed remarkable optimization of its partial FXR agonism to sub‐nanonmolar potency. The resulting FXR modulators lack any activity on CysLT1R and are characterized by high selectivity, high metabolic stability, and low toxicity. With their favorable in vitro profile, these SOSA‐derived FXR modulators constitute a new FXR ligand chemotype that appears suitable for further preclinical evaluation.

Development and in vitro Profiling of Dual FXR/LTA4H Modulators

“…Efficacy refers to maximum FXR activation relative to the activity of 3 μM GW4064 which was defined as 100 % activation. The activity of 13–15 on FXR has been previously reported [25] . Data are the mean±S.E.M., n≥3.…”

“…To obtain a more balanced FXRa/LTA4Hi as tool, we systematically probed the structure‐activity relationship of the dual modulator chemotype with analogues 4 – 20 . The synthesis of 3 , 5 – 11 and 13 – 15 has been reported previously [25] . 12 and 16 – 20 were prepared according to Schemes 2 and 3.…”

“…Consequently, we based further dual SAR elucidation on lead compound 3 . In the lipophilic ether substituent of 3 , stepwise chain shortening from phenylbutyloxy ( 3 ) over phenylpropyloxy ( 8 ), phenylethoxy ( 9 ) and benzyloxy ( 10 ) to phenoxy ( 11 ) had promoted partial FXR agonist potency to single digit nanomolar EC 50 values [25] . Regarding LTA4H inhibition, an optimal chain length was achieved in phenylpropyloxy analogue 8 with 0.14 μM IC 50 value while shorter chains were less active.…”

“…In screening selected compounds of our in‐house collection of FXR ligands for LTA4H inhibition, 3 [25] (Scheme 1 , Table 1 ) evolved as an appealing FXRa/LTA4Hi lead compound with high partial agonist potency on FXR (EC 50 0.026 μM, 34 % efficacy) and intermediate LTA4H inhibitory activity (IC 50 0.54 μM). To obtain a more balanced FXRa/LTA4Hi as tool, we systematically probed the structure‐activity relationship of the dual modulator chemotype with analogues 4 – 20 .…”

“…The synthesis of 3 , 5 – 11 and 13 – 15 has been reported previously. [25] 12 and 16 – 20 were prepared according to Schemes 2 and 3 . For the synthesis of the rigidified dual modulator 12 (Scheme 2 ), 3‐hydroxybiphenyl ( 21 ) was treated with (4‐(ethoxycarbonyl)phenyl)boronic acid ( 22 ) in presence of Cu(OAc) 2 to obtain 23 followed by ester hydrolysis to 24 .…”