1. Heterocyclic ring scaffolds as small-molecule cholesterol absorption inhibitors
Tobias Ritter, Lisbet Kværnø, Moritz Werder, Helmut Hauser and Erick M. Carreira*. Org. Biomol. Chem. , 2005, 3 , 3514–3523
The oxazolidinone scaffold 2 has previously been suggested to serve as a structuralmimic of the β-lactamof ezetimibe (1). Our ab initio geometry optimizations (Fig. 2) additionally suggested that the isoxazoline 3 and the pyrazoline 4 position three out of plane exit vectors in a manner that corresponds well to the b-lactam ring of ezetimibe. The excellent overlaps of the substituents are illustrated by superposition of each of the three heterocycles 2–4 with the b-lactam core found in ezetimibe. In order to focus on the exit vectors from the heterocyclic core, the flexible hydroxypropyl side chain in ezetimibe, which is not expected to strongly favor any single conformation,was replaced by a methyl group in the calculations.
2. Metabolism-guided drug design
Antonia F. Stepan, Vincent Mascitti, Kevin Beaumont and Amit S. Kalgutkar*. Med. Chem. Commun., 2013, 4, 631–652
An excellent example of drug design via an understanding of the bioactivity profile of drug metabolites becomes evident with the cholesterol absorption inhibitor ezetimibe (124) (Fig. 33). Discovery eﬀorts that ultimately led to ezetimibe initially began as a program to discover novel inhibitors of acyl coenzyme A cholesterol acyltransferase (ACAT) using rodent animal models as a pharmacology screen (in the absence of relevant in vitro assays to rank order intrinsic potency). An interesting finding in this effort was the robust reduction of serum cholesterol and blockade of hepatic cholesterol accumulation by certain azetidinone derivatives (e.g.,(-)-SCH48461, 119), which had virtually no inhibitory activity against ACAT. A substantial part of the discovery eﬀort was next devoted to the understanding of the molecular target of 119, which was further confounded by the fact that 119 is extensively metabolized in vivo, making it unclear as to what the active species is. Bioactivity profiling using bile from animals dosed with [14C]-119 led to the characterization of several active metabolites of 119, which included phenols (compounds 120–122) derived from the mono- and bis-O-demethylation and even a glucuronide conjugate (123).
3. Black rice and anthocyanins induce inhibition of cholesterol absorption in vitro
Shu-Long Yao, Ying Xu, Yan-Yan Zhang and Yan-Hua Lu*. Food Funct., 2013, 4, 1602–1608
To examine the eﬀect of anthocyanins on cholesterol uptake in enterocytes, Caco-2 cells were used as an in vitro model. In this study, Ezetimibe, an inhibitor of cholesterol uptake across the gut wall, was used as a positive control, and it caused a substantial depression of cholesterol uptake. In Fig. 7, it is shown that both Cy-3-G and Pn-3-G significantly and in a dose dependent manner suppressed cholesterol uptake. At 40 mgmL-1, Pn-3-G resulted in virtually equivalent reduction of cholesterol uptake compared with Ezetimibe.
4. Synthesis of a fluorinated Ezetimibe analogue using radical allylation of α-bromo-α-fluoro-β-lactam
Atsushi Tarui, Ayumi Tanaka, Masakazu Ueo, Kazuyuki Sato, Masaaki Omote and Akira Ando*. New J. Chem., 2015, 39, 9325—9329
Ezetimibe has been attractive as a novel type of antihyperlipidemic agent for a modern adult disease. This type of drug inhibits a transporter for intestinal cholesterol absorption, Niemann–Pick C1 like 1 (NPC1L1). NPC1L1 is known to provide a main route of cholesterol absorption, therefore Ezetimibe has provided a new course of medication different from HMG-CoA reductase inhibitors such as statins. The backbone structure of Ezetimibe has aβ-lactam core and an alkyl side chain at the C3 position of the β-lactam ring (Fig. 1). Many structure–activity relationship (SAR) studies of several azetidinone compounds have been reported during the past two decades, since these compounds are candidate cholesterol absorption inhibitors. Among the candidate compounds, Clader and co-workers have reported that a 3-fluoroazetidinone compound (1) worked well (Fig. 1). However, the synthetic method for the 3-fluoroazetinone core was not described clearly, and there are no reports on the bioactivity of 3-fluoroazetidinone analogues. Nowadays, organofluorine compounds are important in medicinal chemistry, therefore this type of structuremodification is accepted as a standard target modification in modern SAR studies. In this paper, we describe an effective and short synthetic route for a fluorine-containing Ezetimibe analogue on aβ-lactam core using a-brα-bromo-α-fluoro-β-lactam as a key in termediate.