title: Inhibitors of acyl-CoA:cholesterol acyltransferase: novel trisubstituted ureas as hypocholesterolemic agents.
abstract: Our continued interest in developing novel, potent acyl-CoA:cholesterol acyltransferase (ACAT) inhibitors, and our discovery of several active series of disubstituted urea ACAT inhibitors, have led us to investigate a series of trisubstituted ureas that are structural hybrids of our disubstituted series and of a trisubstituted urea ACAT inhibitor series disclosed by scientists at Lederle. This investigation has led to the discovery of novel trisubstituted ureas, several of which inhibit ACAT in the nanomolar range and effectively lower total plasma cholesterol when administered as a diet admixture in an acute model of hypercholesterolemia in rats. One analogue (35) also lowered total cholesterol as efficaciously as CL 277,082 in our chronic hypercholesterolemic rat model. The most notable finding of this study is that the SAR of the trisubstituted ureas diverges from that seen in our previously disclosed disubstituted urea series. This series showed optimal activity with 2,4-difluoro and 2,4,6-trifluoro substitution on the urea N-phenyl, whereas the disubstituted series showed optimal activity with bulky 2,6-disubstitution on the phenyl ring.
authors.affiliation: Department of Medicinal Chemistry, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, MI 48105, USA.
authors.forename: T S
authors.initials: TS
authors.lastname: Purchase
authors.forename: A D
authors.initials: AD
authors.lastname: Essenburg
authors.forename: K L
authors.initials: KL
authors.lastname: Hamelehle
authors.forename: M S
authors.initials: MS
authors.lastname: Hes
authors.forename: A
authors.initials: A
authors.lastname: Holmes
authors.forename: B R
authors.initials: BR
authors.lastname: Krause
authors.forename: R L
authors.initials: RL
authors.lastname: Stanfield
authors.forename: B K
authors.initials: BK
authors.lastname: Trivedi
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000924:Anticholesteremic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D001555:Benzene Derivatives / Q000737:chemistry; D002784:Cholesterol / Q000097:blood; D004032:Diet; D004195:Disease Models, Animal; D005459:Fluorides / Q000737:chemistry; D006937:Hypercholesterolemia / Q000188:drug therapy; D009682:Magnetic Resonance Spectroscopy; D011817:Rabbits; D051381:Rats; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000924:Anticholesteremic Agents; D001555:Benzene Derivatives; D014508:Urea; D002784:Cholesterol; D002785:Sterol O-Acyltransferase; D005459:Fluorides