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.
| Original language | English |
|---|---|
| Pages (from-to) | 10705-10718 |
| Number of pages | 14 |
| Journal | Journal of Medicinal Chemistry |
| Volume | 59 |
| Issue number | 23 |
| DOIs | |
| Publication status | Published - 8 Dec 2016 |
Cite this
}
Revisiting the SAR of the antischistosomal aryl hydantoin (Ro 13-3978). / Wang, Chunkai; Zhao, Qingjie; Vargas, Mireille; Jones, Jeremy O.; White, Karen; Shackleford, David; Chen, Gong; Saunders, Jessica; Ng, Alice; Chiu, Francis; Dong, Yuxiang; Charman, Susan; Keiser, Jennifer; Vennerstrom, Jonathan L.
In: Journal of Medicinal Chemistry, Vol. 59, No. 23, 08.12.2016, p. 10705-10718.Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - Revisiting the SAR of the antischistosomal aryl hydantoin (Ro 13-3978)
AU - Wang, Chunkai
AU - Zhao, Qingjie
AU - Vargas, Mireille
AU - Jones, Jeremy O.
AU - White, Karen
AU - Shackleford, David
AU - Chen, Gong
AU - Saunders, Jessica
AU - Ng, Alice
AU - Chiu, Francis
AU - Dong, Yuxiang
AU - Charman, Susan
AU - Keiser, Jennifer
AU - Vennerstrom, Jonathan L.
PY - 2016/12/8
Y1 - 2016/12/8
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85003443664&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.6b01410
DO - 10.1021/acs.jmedchem.6b01410
M3 - Article
VL - 59
SP - 10705
EP - 10718
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 23
ER -