Revisiting the SAR of the Antischistosomal Aryl Hydantoin (Ro 13-3978)

Abstract

The aryl hydantoin 1 (Ro 13-3978) was identified in the early 1980s as a promising antischistosomal lead compound. However, this series of aryl hydantoins produced antiandrogenic side effects in the host, a not unexpected outcome given their close structural similarity to the antiandrogenic drug nilutamide. Building on the known SAR of this compound series, we now describe a number of analogs of 1 designed to maximize structural diversity guided by incorporation of substructures and functional groups known to diminish ligand–androgen receptor interactions. These analogs had calculated polar surface area (PSA), measured LogD7.4, aqueous kinetic solubility, and estimated plasma protein binding values in ranges predictive of good ADME profiles. The principal SAR insight was that the hydantoin core of 1 is required for high antischistosomal activity. We identified several compounds with high antischistosomal efficacy that were less antiandrogenic than 1. These data provide direction for the ongoing optimization of antischistosomal hydantoins.

Controlling schistosomiasis with praziquantel: How much longer without a viable alternative?

“…Ro 13–3978 is structurally similar to the antiandrogenic drug nilutamide, which has moderate antischistosomal properties [81]. To reduce the antiandrogenic effect, Wang and colleagues designed a number of analogs incorporating substructures and functional groups and identified several compounds with high antischistosomal efficacy that were less antiandrogenic [82]. …”

SAR of a new antischistosomal urea carboxylic acid

“…Similar to 2 , 4 3-13 had no activity against schistosomula (NTS) or cultured adult S. mansoni 9 at a 10 μM concentration (data not shown). In contrast, praziquantel has an LC 50 of 77 nM against adult S. mansoni in vitro.…”

“…Ro 13-3978 has high metabolic stability, 3,4 but when we administered a 100 mg/kg oral dose of this aryl hydantoin to mice, we observed low levels of hydroxymethyl metabolite 1 and urea carboxylic acid 2 , the hydantoin hydrolysis product 5 (Figure 1). Based on AUC 0-24h values, the respective exposures of 1 and 2 were 3 and <1% relative to that of Ro 13-3978.…”

“…Based on AUC 0-24h values, the respective exposures of 1 and 2 were 3 and <1% relative to that of Ro 13-3978. 4 At the same 100 mg/kg dose, metabolite 1 was inactive, whereas 2 reduced worm burden in S. mansoni -infected mice by 67% 4 and thus has some promise as a new antischistosomal chemotype. We now describe physicochemical profiling, in vitro ADME, and in vivo activities against S. mansoni for a number of analogs of urea carboxylic acid 2 ( 3-13 , Table 1) designed to increase antischistosomal efficacy and establish a baseline structure-activity relationship (SAR) for this chemotype.…”

“…The aryl hydantoin Ro 13-3978 is a promising antischistosomal lead compound (Figure 1) despite its weak antiandrogenic properties. 1-4 Although Ro 13-3978 has little effect on cultured adult S. mansoni , 3 it has high oral efficacy against S. mansoni , S. haematobium and S. japonicum in a variety of animal models. 2,3 For example, Ro 13-3978 has a single oral dose ED 50 of 15 mg/kg in the S. mansoni mouse model; in this same model, praziquantel has an ED 50 of 172 mg/kg.…”