avasimibe

Avasimibe is a potent activator of the pregnane X receptor and, consequently, an indirect inducer of CYP3A4 and P-glycoprotein, as well as a potent inhibitor of several cytochrome P450 isoenzymes, including CYP1A2, CYP2C9, and CYP2C19; its spectrum of CYP induction and inhibition is similar to that of rifampicin.{{cite journal |vauthors=Sahi J, Milad MA, Zheng X, Rose KA, Wang H, Stilgenbauer L, Gilbert D, Jolley S, Stern RH, LeCluyse EL |title=Avasimibe induces CYP3A4 and multiple drug resistance protein 1 gene expression through activation of the pregnane X receptor |journal=J Pharmacol Exp Ther |volume=306 |issue=3 |pages=1027–34 |date=September 2003 |pmid=12766253 |doi=10.1124/jpet.103.050526|s2cid=42853570 }}{{cite journal |vauthors=Sahi J, Stern RH, Milad MA, Rose KA, Gibson G, Zheng X, Stilgenbauer L, Sadagopan N, Jolley S, Gilbert D, LeCluyse EL |title=Effects of avasimibe on cytochrome P450 2C9 expression in vitro and in vivo |journal=Drug Metab Dispos |volume=32 |issue=12 |pages=1370–6 |date=December 2004 |pmid=15333513 |doi=10.1124/dmd.104.000208|s2cid=10168896 }}

Avasimibe is better absorbed when taken with food, especially with a high-fat meal, as reflected by increases in its peak serum concentration and AUC.

Avasimibe was the result of a rational drug design process carried out at Parke-Davis in the early 1990s which sought to obtain orally bioavailable, water-soluble ACAT inhibitors; all such inhibitors known at the time were lipophilic and poorly absorbed when taken by mouth.{{cite journal |vauthors=Sliskovic DR, Krause BR, Picard JA, Anderson M, Bousley RF, Hamelehle KL, Homan R, Julian TN, Rashidbaigi ZA, Stanfield RL |title=Inhibitors of acyl-CoA: cholesterol O-acyl transferase (ACAT) as hypocholesterolemic agents. 6. The first water-soluble ACAT inhibitor with lipid-regulating activity |journal=J Med Chem |volume=37 |issue=5 |pages=560–2 |date=March 1994 |pmid=8126693 |doi=10.1021/jm00031a002}} This process yielded several compounds with potential, including one (designated PD 138142-15) with good solubility in water and remarkable efficacy in animal studies, but it was chemically unstable and degraded rapidly, especially in acidic environments. (Undesirable CYP450 induction was first noted at this time, in PD 138142-15 and its degradation products.{{cite journal |vauthors=Robertson DG, Krause BR, Welty DF, Wolfgang GH, Graziano MJ, Pilcher GD, Urda E |title=Hepatic microsomal induction profile of carbamic acid 2,6-bis(1-methylethyl)phenoxy] sulfonyl]-2,6-bis(1-methylethyl) phenyl ester, monosodium salt (PD138142-15), a novel lipid regulating agent found that avasimibe (then codenamed CI-1011) could be easily manufactured from commercially available starting compounds, and once its efficacy was demonstrated in vitro and in rat studies, it was selected for further development.

After additional safety and preclinical efficacy studies in animals, phase I clinical trials in humans began in 1997, first for hyperlipidemia (June) and subsequently for atherosclerosis (December). Phase II trials for both indications followed in 1998, and phase III trials in 2001.

In October 2003, clinical development of avasimibe was discontinued. Later research discredited the concept of ACAT inhibition as a treatment for dyslipidemia and atherosclerosis, and interest in these compounds as a class waned accordingly.{{cite journal |vauthors=Nissen SE, Tuzcu EM, Brewer HB, Sipahi I, Nicholls SJ, Ganz P, Schoenhagen P, Waters DD, Pepine CJ, Crowe TD, Davidson MH, Deanfield JE, Wisniewski LM, Hanyok JJ, Kassalow LM |title=Effect of ACAT inhibition on the progression of coronary atherosclerosis |journal=N Engl J Med |volume=354 |issue=12 |pages=1253–63 |date=March 2006 |pmid=16554527 |doi=10.1056/NEJMoa054699|doi-access=free }}{{cite journal |vauthors=Rau O, Zettl H, Popescu L, Steinhilber D, Schubert-Zsilavecz M |title=The treatment of dyslipidemia--what's left in the pipeline? |journal=ChemMedChem |volume=3 |issue=2 |pages=206–21 |date=February 2008 |pmid=17963209 |doi=10.1002/cmdc.200700165|s2cid=25244896 }}

Since the termination of its development as an antilipidemic agent, there has been renewed interest in potential repurposing of avasimibe as an antitumor drug{{cite journal |vauthors=Websdale A, Kiew Y, Chalmers P, Chen X, Cioccoloni G, Hughes TA, Luo X, Mwarzi R, Poirot M, Røberg-Larsen H, Wu R, Xu M, Zulyniak MA, Thorne JL |date=February 2022 |title=Pharmacologic and genetic inhibition of cholesterol esterification enzymes reduces tumour burden: A systematic review and meta-analysis of preclinical models |url=https://eprints.whiterose.ac.uk/177472/7/CRediT.pdf |journal=Biochem Pharmacol |volume=196 |issue= |pages=114731 |doi=10.1016/j.bcp.2021.114731 |pmid=34407453 |s2cid=237215690 |archive-url= |archive-date= |access-date=15 August 2022 |url-status= }}{{cite journal |vauthors=Zabielska J, Sledzinski T, Stelmanska E |title=Acyl-Coenzyme A: Cholesterol Acyltransferase Inhibition in Cancer Treatment |journal=Anticancer Res |volume=39 |issue=7 |pages=3385–3394 |date=July 2019 |pmid=31262860 |doi=10.21873/anticanres.13482|s2cid=195771341 |doi-access=free }} and to prevent or treat bacterial infections by decreasing bacterial virulence.{{cite journal |vauthors=Hasan MK, El Qaidi S, McDonald P, Roy A, Hardwidge PR |title=Repurposing Avasimibe to Inhibit Bacterial Glycosyltransferases |journal=Pathogens |volume=11 |issue=3 |date=March 2022 |page=370 |pmid=35335693 |pmc=8953086 |doi=10.3390/pathogens11030370|doi-access=free }} {{As of|2022}}, these potential indications remain in preclinical research.

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Category:Hypolipidemic agents

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Category:Sulfamate esters

Category:Terpenes and terpenoids