Anacetrapib

Clinical trials[edit]
At the 16th International Symposium on Drugs Affecting Lipid Metabolism (New York, Oct 4-7, 2007), Merck reported on a Phase IIb STUDY. The eight week study reported dosage correlated reduction in LDL-C and increases in HDL-C levels with no corresponding increases in BLOOD PRESSURE in any cohort. The increase in HDL was particularly significant, averaging 44 percent, 86 percent, 139 percent and 133 percent at doses of 10 mg, 40 mg, 150 mg and 300 mg.

Merck performed a dose-ranging study of anacetrapib,[3] with the RESULTS PRESENTED in 2009.[4] A 2013 study of 407 Japanese patients found anacetrapib reduced LDL and raised HDL alone or with atorvastatin.[5]

Phase III trial (DEFINE)[edit]
Merck started a Phase III trial to ASSESS the drug's effects on LDL, HDL, clinically measurable cardiovascular events, and safety;[6] It was code-named DEFINE (Determining the Efficacy and Tolerability of CETP Inhibition with Anacetrapib), and was described as a medium sized safety and efficacy trial.[7]

Early results from the DEFINE trial were presented on November 17 at AHA2010, a meeting of the American Heart Association. At 100 mg dosage, LDL decreased by 36%, lipoprotein(a) decreased by 36.4%, while HDL increased by 138%. Systolic blood pressure showed no increase, and there was no association with increased CVD death or events.[8] The results were later updated to 39.8% of LDL decrease.[9]

Cardiologist Steve Nissen described DEFINE as a medium-sized safety trial intended to find out "whether anacetrapib would show the same increase in adverse cardiovascular events that was seen with torcetrapib." Fortunately, anacetrapib did not. In his opinion the DEFINE study was too small to show a clear benefit, but the trends in the major adverse cardiovascular events were going in the right direction.[10]

A two year follow up is due to COMPLETE by December 2012. A 2014 study found HDL and drug levels remained elevated 2 to 4 years after discontinuation.[11]

Phase III trial (REVEAL)[edit]
The REVEAL (Randomized EValuation of THE EFFECTS of Anacetrapib Through Lipid-modification) will assess whether there is CLINICAL benefit associated with anacetrapib. REVEAL recruited 30,000 PARTICIPANTS[12] for a randomized, double-blinded, placebo-controlled trial.

The study will compare patients with a history of vascular disease (such as heart disease, cerebrovascular disease, and peripheral vascular disease) on 100 mg of anacetrapib daily to those on placebo, to determine if the addition of anacetrapib reduces the risk of major coronary events (such as HEART ATTACK, death from heart disease, or requiring a coronary revascularization.) Data will be collected through 2017.[13]

A concern raised in October 2013 is related to the time that the drug remains in people's body after they stop taking it. The report shows that even after 4 years the levels of the medicine were still detectable.[14]

See also[edit]
Other CETP inhibitors:

Torcetrapib was developed by Pfizer until December 2006 but caused unacceptable increases in BLOOD PRESSURE and had net cardiovascular detriment.
Dalcetrapib was developed by Hoffmann–La Roche until May 2012. It did not raise blood pressure and did raise HDL, but it showed no clinically meaningful efficacy.
Evacetrapib is under development by Eli Lilly & Company.

Amflutizole

Amflutizole is a xanthine oxidase inhibitor used for the treatment of gout.

Synthesis[edit]
Amflutizole synth.png

The tosyl oxime of the meta-trifluromethyl benzoic acid acid cyanide is the reactamt. This is cross reacted with ethyl 2-mercaptoacetate in the presence of a base; displacement of the tosylate by mercaptide leads to the formation of the heterocyclic N–S bond. This intermediate compound is then converted to the carbanion by a second equivalent of base. This adds to the cyano group; protonation then goes on to form the imine, tautomerization of which gives the corresponding amino form. Finally, saponification of the ester thus affords amflutizole as the product.[1]

Amphetaminil

Amphetaminil (Aponeuron, AN-1) is a stimulant drug derived from amphetamine, which was developed in the 1970s and used for the treatment of obesity,[1] ADHD,[2][3] and narcolepsy.[4] It has largely been withdrawn from clinical use following problems with abuse.[5]

Amphetamine

Amphetamine[note 1] (pronunciation: Listeni/æmˈfɛtəmiːn/; contracted from alpha‑methylphenethylamine) is a potent central nervous system (CNS) stimulant of the phenethylamine class that is used in the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy. Amphetamine was discovered in 1887 and exists as two enantiomers: levoamphetamine and dextroamphetamine.[note 2] Amphetamine properly refers to a specific chemical, the racemic free base, which is equal parts of the two enantiomers, levoamphetamine and dextroamphetamine, in their pure amine forms. However, the term is frequently used informally to refer to any combination of the enantiomers, or to either of them alone. Historically, it has been used to treat nasal congestion, depression, and obesity. Amphetamine is also used as a performance and cognitive enhancer, and recreationally as an aphrodisiac and euphoriant. It is a prescription medication in many countries, and unauthorized possession and distribution of amphetamine are often tightly controlled due to the significant health risks associated with substance abuse.[sources 1]

The first pharmaceutical amphetamine was Benzedrine, a brand of inhalers used to treat a variety of conditions. Currently, pharmaceutical amphetamine is typically prescribed as Adderall,[note 3] dextroamphetamine, or the inactive prodrug lisdexamfetamine. Amphetamine, through activation of a trace amine receptor, increases biogenic amine and excitatory neurotransmitter activity in the brain, with its most pronounced effects targeting the catecholamine neurotransmitters norepinephrine and dopamine. At therapeutic doses, this causes emotional and cognitive effects such as euphoria, change in libido, increased wakefulness, and improved cognitive control. It induces physical effects such as decreased reaction time, fatigue resistance, and increased muscle strength.[sources 2]

Much larger doses of amphetamine are likely to impair cognitive function and induce rapid muscle breakdown. Drug addiction is a serious risk with large recreational doses, but rarely arises from medical use. Very high doses can result in psychosis (e.g., delusions and paranoia) which rarely occurs at therapeutic doses even during long-term use. Recreational doses are generally much larger than prescribed therapeutic doses and carry a far greater risk of serious side effects.[sources 3]

Amphetamine is also the parent compound of its own structural class, the substituted amphetamines,[note 4] which includes prominent substances such as bupropion, cathinone, MDMA (ecstasy), and methamphetamine. As a member of the phenethylamine class, amphetamine is also chemically related to the naturally occurring trace amine neuromodulators, specifically phenethylamine[note 5] and N-methylphenethylamine, both of which are produced within the human body. Phenethylamine is the parent compound of amphetamine, while N-methylphenethylamine is a constitutional isomer that differs only in the placement of the methyl group.[sources 4]

Amfepramone

Amfepramone (INN)[note 1] is a stimulant drug of the phenethylamine, amphetamine, and cathinone classes that is used as an appetite suppressant.[2][3] It is used in the short-term management of obesity, along with dietary and lifestyle changes.[2] Amfepramone is most closely chemically related to the antidepressant and smoking cessation aid bupropion (previously called amfebutamone), which has also been developed as a weight-loss medicine when in a combination product with naltrexone.

Amfepentorex

Amfepentorex is a stimulant drug derived from methamphetamine which is used as an appetite suppressant for the treatment of obesity. Dosage is 50–100 mg per day. Side effects include insomnia, hypertension and acute glaucoma.

Amfecloral

Amfecloral (INN), also known as amphecloral (USAN), is a stimulant drug of the phenethylamine and amphetamine chemical classes that was used as an appetite suppressant under the trade name Acutran, but is now no longer marketed.[1] It acts as a prodrug which splits to form amphetamine and chloral hydrate, similarly to clobenzorex and related compounds, except that the N-substituent in this case yields a compound that is active in its own right. The chloral hydrate metabolite is a gabaminergic sedative/hypnotic, and would in theory counteract some of the stimulant effects of the amphetamine metabolite. This would produce an effect similar to the amphetamine/barbiturate combinations previously used in psychiatric medications.