Design, synthesis, and biological evaluation of thio-containing compounds with serum HDL-cholesterol-elevating properties.
A novel series of substituted sulfanyldihydroimidazolones (1) that modulates high-density lipoprotein cholesterol (HDL-C) has been reported to have HDL-elevating properties in several animal models. Concerns about the chemical and metabolic stability of 1 directed us to explore the structure-activity relationship (SAR) of a related series of substituted thiohydantoins (2). Expansion of the scope of the thiohydantoin series led to exploration of compounds in related thio-containing ring systems 3-7 and the N-cyanoguanidine derivative 8. Compounds were tested sequentially in three animal models to assess their HDL-C elevating efficacy and safety profiles. Further evaluation of selected compounds in a dose-response paradigm culminated in the identification of compound 2.39 as a candidate compound for advanced preclinical studies.
Elokdah
Hassan
H
Medicinal Chemistry, Wyeth Research, CN 8000, Princeton, New Jersey 08543, USA. elokdah@wyeth.com
Sulkowski
Theodore S
TS
Abou-Gharbia
Magid
M
Butera
John A
JA
Chai
Sie-Yearl
SY
McFarlane
Geraldine R
GR
McKean
Mar-Lee
ML
Babiak
John L
JL
Adelman
Steven J
SJ
Quinet
Elaine M
EM
D000284:Administration, Oral; D000818:Animals; D008076:Cholesterol, HDL / Q000097:blood*; D006224:Cricetinae; D015195:Drug Design; D006146:Guanidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006937:Hypercholesterolemia / Q000097:blood; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013268:Stimulation, Chemical; D013329:Structure-Activity Relationship; D045162:Thiazolidinediones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013867:Thiohydantoins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013871:Thiones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
C482798:3-(5-chloro-2-methylphenyl)-1-ethyl-2-thioxoimidazolidin-4-one; D008076:Cholesterol, HDL; D006146:Guanidines; D007093:Imidazoles; D010879:Piperazines; D011743:Pyrimidines; D045162:Thiazolidinediones; D013867:Thiohydantoins; D013871:Thiones; C004711:dicyandiamido