Foundations for blockbuster drugs in federally sponsored research

Abstract

'Blockbuster' drugs, which are widely prescribed and improve the health of millions, often originate in fundamental laboratory research. An important example of such drugs are the cholesterol-lowering drugs called 'statins', including Zocor, Pravachol, and Lipitor, which millions of people take in the U.S. every year. This short paper outlines the direct and indirect contributions of federally sponsored research to the development of these important drugs.

Reaction of acetophenone and benzylphenylketone oximes with phenylacetylene: synthesis of di- and triphenylpyrroles

“…The formation of two isomeric triphenylpyrroles 6 and 7 may be rationalized by cyclization (via [3,3]-sigmatropic rearrangement) of isomeric O-vinylketoximes 9 and 10, the primary adducts of oxime 2 to acetylene 3 (Scheme 3). Such a mechanism was experimentally proved in a number of previous works 4,13f,17 where the similar intermediate O-vinyloximes were isolated and separately rearranged to the corresponding pyrroles.…”

“…Phenylacetylene (16.85 g, 0.165 mol) was added to the formed lithium oximate solution, temperature of the mixture was raised to 137-140 o C and the reaction mixture was stirred during 6 h. After cooling up to room temperature the reaction mixture was diluted with water and extracted with diethyl ether (50 ml x 5). The ether extracts were washed with water (50 ml x 3) and dried over K 2 CO 3 . The residue after removal of diethyl ether was distillated in vacuo (2 mm Hg) to remove acetophenone formed (9.94 g, 55%) and then rectified in fine vacuo (6 .…”

“…For example, the cholesterol reduction drug lipitor (atorvastatin), one of the most commonly used in the United States, contains a 2,3-diphenylpyrrole motif. 2а, 3 A series of 2,3,4-triphenylpyrrole derivatives exert high hypoglycemic action and can be recommended for diabetes treatment. 2а Although arylpyrroles are applied for the synthesis of fluorescent azaindacene dyes of BODIPY family 4 as well as optoelectronic materials, 5 it is their pharmacological appeal that seems to be the chief reason for a steady interest in the development of synthetic procedures for these compounds, reported, in particular, in reviews.…”

Solid Phase and Combinatorial Chemistry in the Heterocyclic Field

“…A further element of diversity can be introduced into the pyrrolidine ring during the cleavage step (multidirectional electrophilic cleavage) with different electrophiles (HCl, acid chlorides, allyl iodide, and so on) to furnish collections of pyrrolidines of type 124 in good yields (Scheme 28.38) [159]. Substituted pyrroles are commonly found in natural products [160,161], drugs [162,163], conducting materials [164,165] and insecticides [166]. The pyrrole ring system has been synthesized on solid-supports by few methods.…”

Synthesis and Evaluation of the Cytotoxic Activities of Some Isatin Derivatives

“…4) This substance has been reported to possess a wide range of central nervous system activities. 5,6) Moreover, -isatin moiety is present in numerous medicinal agents that display broad spectrum of biological properties, such as antiviral, 7,8) antifungal, 9) antibacterial, 10,11) anticancer, [12][13][14][15][16][17][18][19] anti-poxvirus, 20) and antiproliferation activities. 21) Owing to its chemical reactivity profile and, in particular to the electrophilicity of its C-3 carbonyl group; isatin has been transformed to a wide variety of biologically active 3-substituted indoline-2-ones.…”