TY - JOUR
T1 - Spiroimidazolidinone NPC1L1 inhibitors. Part 2
T2 - Structure-activity studies and in vivo efficacy
AU - Howell, Kobporn L.
AU - Devita, Robert J.
AU - Garcia-Calvo, Margarita
AU - Meurer, Roger D.
AU - Lisnock, Jeanmarie
AU - Bull, Herbert G.
AU - McMasters, Daniel R.
AU - McCann, Margaret E.
AU - Mills, Sander G.
PY - 2010/12/1
Y1 - 2010/12/1
N2 - Ezetimibe (Zetia®), a cholesterol-absorption inhibitor (CAI) approved by the FDA for the treatment of hypercholesterolemia, is believed to target the intestine protein Niemann-Pick C1-Like 1 (NPC1L1) or its pathway. A spiroimidazolidinone NPC1L1 inhibitor identified by virtual screening showed moderate binding activity but was not efficacious in an in vivo rodent model of cholesterol absorption. Synthesis of analogs established the structure-activity relationships for binding activity, and resulted in compounds with in vivo efficacy, including 24, which inhibited plasma cholesterol absorption by 67% in the mouse, thereby providing proof-of-concept that non-β-lactams can be effective CAIs.
AB - Ezetimibe (Zetia®), a cholesterol-absorption inhibitor (CAI) approved by the FDA for the treatment of hypercholesterolemia, is believed to target the intestine protein Niemann-Pick C1-Like 1 (NPC1L1) or its pathway. A spiroimidazolidinone NPC1L1 inhibitor identified by virtual screening showed moderate binding activity but was not efficacious in an in vivo rodent model of cholesterol absorption. Synthesis of analogs established the structure-activity relationships for binding activity, and resulted in compounds with in vivo efficacy, including 24, which inhibited plasma cholesterol absorption by 67% in the mouse, thereby providing proof-of-concept that non-β-lactams can be effective CAIs.
KW - Cholesterol-absorption inhibitor
KW - Ezetimibe
KW - Hypercholesterolemia
KW - Niemann-Pick C1-Like 1 protein
KW - Spiroimidazolidinone
UR - https://www.scopus.com/pages/publications/78149281356
U2 - 10.1016/j.bmcl.2010.09.138
DO - 10.1016/j.bmcl.2010.09.138
M3 - Article
C2 - 21030254
AN - SCOPUS:78149281356
SN - 0960-894X
VL - 20
SP - 6929
EP - 6932
JO - Bioorganic and Medicinal Chemistry Letters
JF - Bioorganic and Medicinal Chemistry Letters
IS - 23
ER -