Beta-blockers development

Bufuralol (11) is a p-adrcnoccptor agent (beta-blocker), developed by Roche [8,9], As part of a continuing program on the synthesis of substrates and metabolites for Cytochrome P450 studies, we wished to prepare both optically active bufuralol and an important metabolite, the hydroxybufuralol (12). This brief account of our efforts illustrates the way in which classical resolution is giving way to asymmetric synthesis, whether mediated by synthetic chiral auxiliaries, conventional catalysts, or enzymes. 

The success of quinine inspired the search for other antimalarials. The greatest impetus for the development of synthetic dmgs came this century when the two World Wars intermpted the supply of cinchona bark to the combatants. A stmcturally related 4-quinolinemethanol is mefloquine (65, Lariam [51773-92-3]) which now serves as an effective alternative agent for chloroquine-resistant P. falciparum. This is a potent substance that requires less than one-tenth the dose of quinine to effect cures. There are some untoward side effects associated with this dmg such as gastrointestinal upset and dizziness, but they tend to be transient. Mefloquine is not recommended for use by those using beta-blockers, those whose job requires fine coordination and spatial discrimination, or those with a history of epilepsy or psychiatric disorders. A combination of mefloquine with Fansidar (a mixture of pyrimethamine and sulfadoxine) is known as Fansimef but its use is not recommended. Resistance to mefloquine has been reported even though the compound has not been in wide use. 

Pindolol. The antihypertensive beta-blocker pindolol was studied in 32 subjects in a crossover study comparing pindolol (20 mg, twice daily), methylphenidate, and placebo (Buitelaar et al., 1996). Pindolol significantly reduced ADHD symptoms, but two subjects developed nightmares and hallucinations on the medication. Because lower doses were not examined in this study, it is possible that lower doses may be effective and better tolerated. 

Over the next 20 years, the benzodiazepines, TCAs, MAOIs, and beta-blockers were used to treat anxiety disorders. By the mid-1980s, up to 10% of all Americans were taking a benzodiazepine. In 1988, fluoxetine (Prozac) was introduced by Eli Lilly as the first selective serotonin reuptake inhibitor (SSRI) for the treatment of mood and anxiety disorders. Its success led to the development of several other SSRI drugs. Today, these drugs are the first line of drug treatment for most anxiety disorders. 

A 48-year-old woman developed palpitation and insomnia. The clinical history, physical examination, and laboratory tests supported hyperthyroidism. Since July 1994 she had been combating constipation by improper use of an iodine-containing antiseptic cream for external use only. She had inserted povidone-iodine into her rectum by means of a cannula. The iodine-containing cream was withdrawn and she was given a beta-blocker. The palpitation resolved within 2 weeks and her plasma thyroid hormone concentrations normalized within 1 month. 

Ophthalmic beta-blockers can cause hypoglycemia in insulin-dependent diabetes (212). Conversely, in diabetic patients taking oral hypoglycemic drugs, hyperglycemia can develop because of impaired insulin secretion (SEDA-21, 487). 

Ohlstein EH, Romanic AM. New developments in the use of beta-blockers for the management of heart failure. Expert Opin Investig Drugs. 2004 13 999-1005. 

Diastereomeric complexes can also be formed by ion-pairing of an enantiomer with a chiral counterion. In order to form this diastereomeric complex, it has been postulated that at least three interaction points between the ion pair are required [250]. Nearly all of these form weak complexes in aqueous mobile phases. Consequently, the chromatographic methods that have been developed have been either silica or diol columns with low-polarity mobile phases. Enantiomeric amines, such as the beta-blockers, have been optically resolved when (-l-)-lO-camphorsulfonic acid was used as the chiral counterion [251]. Enantiomers of norephedrine, ephedrine, pseudoephedrine, and phenyramidol have all been resolved from their respective enantiomers with n-dibutyltartrate [252]. Enantiomers of naproxen, a chiral carboxylic acid, are resolved from each other by either using quinidine or quinine in the mobile phase [253]. In these studies, silica... 

V. Rein, Drugs Looking for Diseases, Innovative Drug Research and the Development of the Beta Blockers and the Calcium Antagonists, Kluwer Academic, Dordrecht, 1991. 

Hypertension and type 2 diabetes mellitus are frequent co-morbid conditions resulting in a very high risk population. ARBs - losartan as compared to the beta-blocker atenolol in the LIFE Study [8], candesartan as compared to the control therapies in the SCOPE [16] and CHARM [33] Studies, valsartan as compared to amlodipine in the VALUE Study [34] have been found to have beneficial effects in preventing the development of type 2 diabetes mellitus. 

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