Avasimibe
 | |
| Clinical data | |
|---|---|
| Other names | 2,6-diisopropylphenyl (2-(2,4,6-triisopropylphenyl)acetyl)sulfamate |
| Routes of administration | Oral |
| ATC code | |
| Legal status | |
| Legal status |
|
| Pharmacokinetic data | |
| Metabolism | Hepatic (CYP3A4, 2C9) |
| Elimination half-life | 15–24 hours |
| Excretion | Fecal (predominant), renal (<2%) |
| Identifiers | |
| |
| CAS Number | |
| PubChem CID | |
| DrugBank | |
| ChemSpider | |
| UNII | |
| KEGG | |
| ChEBI | |
| ChEMBL | |
| Chemical and physical data | |
| Formula | C29H43NO4S |
| Molar mass | 501.73 g·mol−1 |
| 3D model (JSmol) | |
| |
| |
Avasimibe (INN), codenamed CI 1011, is a drug that inhibits sterol O-acyltransferases (SOAT1 and SOAT2, also known as ACAT1 and ACAT2), enzymes involved in the metabolism and catabolism of cholesterol. It was discovered by Parke-Davis (later Pfizer) and developed as a possible lipid-lowering agent and treatment for atherosclerosis.[1]
The first description of avasimibe was published in 1996.[2] Clinical trials began in 1997.[1] However, development was halted in 2003 due to a high potential for interactions with other medicines,[3] and a pivotal study found it had no favorable effect on atherosclerosis and actually increased LDL cholesterol levels significantly.[4]
SOAT/ACAT inhibition has since been discredited as a viable strategy for treating high cholesterol and atherosclerosis,[5] but renewed interest in avasimibe has arisen due to its potential antitumor utility through other mechanisms.
It has never been marketed or used outside clinical trials.[6]
Pharmacology
[edit]Mechanism of action
[edit]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.[7][8]
Pharmacokinetics
[edit]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.[1]
History
[edit]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.[9] 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.[2] (Undesirable CYP450 induction was first noted at this time, in PD 138142-15 and its degradation products.[2][10]) Chemical modification of PD 138142-15 and retrosynthetic analysis 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.[2]
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).[1][6] Phase II trials for both indications followed in 1998, and phase III trials in 2001.[1][6]
In October 2003, clinical development of avasimibe was discontinued.[6] 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.[11][5]
Research
[edit]Since the termination of its development as an antilipidemic agent, there has been renewed interest in potential repurposing of avasimibe as an antitumor drug[12][13] and to prevent or treat bacterial infections by decreasing bacterial virulence.[14] As of 2022[update], these potential indications remain in preclinical research.
References
[edit]- ^ a b c d e [No authors listed] (2002). "Avasimibe. CI 1011". Drugs in R&D. 3 (3): 173–4. doi:10.2165/00126839-200203030-00005. PMID 12099161.
- ^ a b c d Lee HT, Sliskovic DR, Picard JA, Roth BD, Wierenga W, Hicks JL, Bousley RF, Hamelehle KL, Homan R, Speyer C, Stanfield RL, Krause BR (December 1996). "Inhibitors of acyl-CoA: cholesterol O-acyl transferase (ACAT) as hypocholesterolemic agents. CI-1011: an acyl sulfamate with unique cholesterol-lowering activity in animals fed noncholesterol-supplemented diets". J Med Chem. 39 (26): 5031–4. doi:10.1021/jm960674d. PMID 8978833.
- ^ "Avasimibe (Code C75252)". NCI Thesaurus. Retrieved 2022-05-09.
This article incorporates text from this source, which is in the public domain.
- ^ Tardif JC, Grégoire J, L'Allier PL, Anderson TJ, Bertrand O, Reeves F, Title LM, Alfonso F, Schampaert E, Hassan A, McLain R, Pressler ML, Ibrahim R, Lespérance J, Blue J, Heinonen T, Rodés-Cabau J (November 2004). "Effects of the acyl coenzyme A:cholesterol acyltransferase inhibitor avasimibe on human atherosclerotic lesions". Circulation. 110 (21): 3372–7. doi:10.1161/01.CIR.0000147777.12010.EF. PMID 15533865. S2CID 9821021.
- ^ a b Rau O, Zettl H, Popescu L, Steinhilber D, Schubert-Zsilavecz M (February 2008). "The treatment of dyslipidemia--what's left in the pipeline?". ChemMedChem. 3 (2): 206–21. doi:10.1002/cmdc.200700165. PMID 17963209. S2CID 25244896.
- ^ a b c d "Drug Profile: Avasimibe" (PDF). AdisInsight. 2003-10-28. Retrieved 2022-05-09.
- ^ Sahi J, Milad MA, Zheng X, Rose KA, Wang H, Stilgenbauer L, Gilbert D, Jolley S, Stern RH, LeCluyse EL (September 2003). "Avasimibe induces CYP3A4 and multiple drug resistance protein 1 gene expression through activation of the pregnane X receptor". J Pharmacol Exp Ther. 306 (3): 1027–34. doi:10.1124/jpet.103.050526. PMID 12766253. S2CID 42853570.
- ^ Sahi J, Stern RH, Milad MA, Rose KA, Gibson G, Zheng X, Stilgenbauer L, Sadagopan N, Jolley S, Gilbert D, LeCluyse EL (December 2004). "Effects of avasimibe on cytochrome P450 2C9 expression in vitro and in vivo". Drug Metab Dispos. 32 (12): 1370–6. doi:10.1124/dmd.104.000208. PMID 15333513. S2CID 10168896.
- ^ Sliskovic DR, Krause BR, Picard JA, Anderson M, Bousley RF, Hamelehle KL, Homan R, Julian TN, Rashidbaigi ZA, Stanfield RL (March 1994). "Inhibitors of acyl-CoA: cholesterol O-acyl transferase (ACAT) as hypocholesterolemic agents. 6. The first water-soluble ACAT inhibitor with lipid-regulating activity". J Med Chem. 37 (5): 560–2. doi:10.1021/jm00031a002. PMID 8126693.
- ^ Robertson DG, Krause BR, Welty DF, Wolfgang GH, Graziano MJ, Pilcher GD, Urda E (March 1995). "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". Biochem Pharmacol. 49 (6): 799–808. doi:10.1016/0006-2952(94)00540-3. PMID 7702638.
- ^ 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 (March 2006). "Effect of ACAT inhibition on the progression of coronary atherosclerosis". N Engl J Med. 354 (12): 1253–63. doi:10.1056/NEJMoa054699. PMID 16554527.
- ^ 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 (February 2022). "Pharmacologic and genetic inhibition of cholesterol esterification enzymes reduces tumour burden: A systematic review and meta-analysis of preclinical models" (PDF). Biochem Pharmacol. 196: 114731. doi:10.1016/j.bcp.2021.114731. PMID 34407453. S2CID 237215690. Retrieved 15 August 2022.
- ^ Zabielska J, Sledzinski T, Stelmanska E (July 2019). "Acyl-Coenzyme A: Cholesterol Acyltransferase Inhibition in Cancer Treatment". Anticancer Res. 39 (7): 3385–3394. doi:10.21873/anticanres.13482. PMID 31262860. S2CID 195771341.
- ^ Hasan MK, El Qaidi S, McDonald P, Roy A, Hardwidge PR (March 2022). "Repurposing Avasimibe to Inhibit Bacterial Glycosyltransferases". Pathogens. 11 (3): 370. doi:10.3390/pathogens11030370. PMC 8953086. PMID 35335693.