Inhibitors of cholesterol biosynthesis. 2. 1,3,5-Trisubstituted [2-(tetrahydro-4-hydroxy-2-oxopyran-6-yl)ethyl]pyrazoles

Dr, Sliskovic; Bd, Roth; Mw, Wilson; Ml, Hoefle; Rs, Newton

doi:10.1021/jm00163a006

Cited by 56 publications

(14 citation statements)

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“…These structures represent indispensable components of the modern medicinal chemistry repertoire 2. Pyrazoles, while rarely found in nature, serve as important core structures of many pharmaceuticals and pharmaceutical leads with a wide range of biological activities (e.g., cholesterol lowering,3 anti-inflammatory,4 anti-cancer,5 anti-depressant and anti-psychotic agents6). As a result, there is a continuing interest in the development of versatile methods to access highly substituted pyrazoles.…”

Section: Introductionmentioning

confidence: 99%

C−H Bonds as Ubiquitous Functionality: A General Approach to Complex Arylated Pyrazoles via Sequential Regioselective C-Arylation and N-Alkylation Enabled by SEM-Group Transposition

2009

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Pyrazoles are important azole heteroarenes frequently found in pharmaceuticals and protein ligands and there has been a growing interest in new synthetic methods for their preparation. We report the first catalytic intermolecular C-H arylation of pyrazoles, namely SEM-protected pyrazoles and N-alkylpyrazoles, which lays the foundation for a new approach to the synthesis of complex arylated pyrazoles, where new arene rings are directly attached to predetermined positions of the heteroarene nucleus. Through a systematic search we identified a palladium-pivalate catalytic system as the most effective protocol and mapped the reactivity of all three C-H bonds of the pyrazole (C-5 > C-4 ≫ C-3). To circumvent the low reactivity of C-3 position, we developed a “SEM switch”, which transposes the SEM-protecting group from one nitrogen to the other in one step, and in the process transforms the unreactive C-3 position to the reactive C-5 position. The SEM switch thus enables sequential arylation of C-5 and C-3 position, providing rapid access to protected or free 3,4,5-triarylpyrazoles (C-4 arene ring is readily introduced by bromination and Suzuki coupling). Furthermore, N-alkylation of SEM-protected pyrazoles allows for regioselective introduction of the amine substituent, addressing the low regioselectivity of N-alkylation of pyrazoles lacking sufficient steric bias. Thus, the catalytic C-H arylation combined with the protecting group transposition and N-alkylation provides a rapid route to fully substituted pyrazoles with complete regiocontrol of all substituents. The particular strength of this strategy is the ability to commence the synthesis from either the parent pyrazole or practically any pyrazole intermediate.

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Section: Introductionmentioning

confidence: 99%

C−H Bonds as Ubiquitous Functionality: A General Approach to Complex Arylated Pyrazoles via Sequential Regioselective C-Arylation and N-Alkylation Enabled by SEM-Group Transposition

2009

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“…These reports were followed up by scientists at the then Parke-Davis division of Warner-Lambert, well before the takeover by Pfizer, demonstrating that the same 'natural product warhead' as in mevinolin, coupled to either fluorophenyl-substituted pyrroles [51] or 1,3,5-trisubstituted triazoles [52], were also active entities, basically comparable to compactin, although reference to the patent literature shows that a Sandoz scientist had filed a US patent in 1985 (issued in 1986) [101] covering the pyrazole nucleus. Contemporaneously, Rosen and Heathcock published an excellent review covering the synthesis of mevinic acids that also showed some of the early 'synthetic derivatives of mevinolin' [53].…”

Section: Anticholesterolemicsmentioning

confidence: 99%

Natural Product Scaffolds as Leads to Drugs

Newman

Cragg

2009

Future Med. Chem.

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Numerous 'scaffolds' that have been identified in natural product structures have led to very significant numbers of approved drugs and drug candidates for a multiplicity of diseases over the years. In this mini-review, we discuss the base scaffolds (chemical skeletons) that we feel have produced very significant numbers of agents as drugs or drug leads and, in a number of cases, compounds that can be used as chemical synthons or that present activities in biological areas that were not obvious from their earlier history.

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“…For these experiments, we used PD123588, a compound that is structurally dissimilar to lovastatin ( Fig. 2) and is slightly less active than both lovastatin and simvastatin in its effectiveness of inhibiting HMG-R in vitro (Alberts et al, 1980;Endo, 1980;Sliskovic et al, 1990;Endo, 1992). As was the case for lovastatin, PD123588 acted to block clam oocyte activation ( Fig.…”

Section: Inhibitors Of Hmg-coa Reductase Activity Block Activation Ofmentioning

confidence: 99%

“…Two types of HMG-R inhibitors mainly are used in this study, lovastatin and PD123588. Both lovastatin, which is isolated as a fungal metabolite (Alberts et al, 1980;Endo, 1980) and PD123588, which is synthetically derived (compound 10 in [Sliskovic et al, 1990]), were developed independently for use as drugs effective in lowering plasma cholesterol in hypercholesterolemic patients. They act to inhibit HMG-R, a microsomal enzyme that catalyzes the reduction of HMG-CoA to mevalonate, which is the ratelimiting step in the synthesis of cholesterol (Goldstein and Brown, 1977).…”

Section: Mechanisms Of Action For Hmg-r Inhibitorsmentioning

confidence: 99%

Oocyte activation and passage through the metaphase/anaphase transition of the meiotic cell cycle is blocked in clams by inhibitors of HMG-CoA reductase activity.

Turner

Minkoff

Martin

et al. 1995

The Journal of Cell Biology

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Abstract. Cell cycle progression for postembryonic cells requires the activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-R), the enzyme which catalyzes the production of the isoprenoid precursor, mevalonate. In this study, we examine the requirements of HMG-R activity for cell cycle progression during the meiotic and early mitotic divisions using oocytes and dividing embryos from the surf clam, Spisula solidissima. Using two different inhibitors of HMG-R, we find that the activity of this enzyme appears to be required at three distinct points of the cell cycle during meiosis. Depending on the stage at which these inhibitors are added to synchronous clam cultures, a reversible cell cycle block is triggered at the time of activation or at metaphase of either meiosis I or II, whereas there is no block to the mitotic cell cycle. Inhibition of HMG-R activity in activated oocytes does not affect the transient activation of p42 MAPK but results in a block at metaphase of meiosis I that is accompanied by the stabilization of cyclins A and B and p34 ~c2 kinase activity. Our results suggest that metabolites from the mevalonate biosynthetic pathway can act to influence the process of activation, as well as the events later in the cell cycle that lead to cyclin proteolysis and the exit from M phase during clam meiosis.p ROGRESS through the cell cycle of postembryonic cells requires the activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-R) t (for reviews see Goldstein and Brown, 1990;Maltese, 1990). HMG-R is a microsomal enzyme which catalyzes the reduction of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) to mevalonate, an essential precursor required for the biosynthesis of several vital end products, which include: cholesterol and other sterols, important for membrane replication and structure; dolichol, required for N-linked protein glycosylation; isopentenyladenine, which is present in some types of tRNAs; and the isoprenoid side-chains of ubiquinone and heme-a, which are involved in electron transport

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Inhibitors of cholesterol biosynthesis. 2. 1,3,5-Trisubstituted [2-(tetrahydro-4-hydroxy-2-oxopyran-6-yl)ethyl]pyrazoles

Cited by 56 publications

References 0 publications

C−H Bonds as Ubiquitous Functionality: A General Approach to Complex Arylated Pyrazoles via Sequential Regioselective C-Arylation and N-Alkylation Enabled by SEM-Group Transposition

C−H Bonds as Ubiquitous Functionality: A General Approach to Complex Arylated Pyrazoles via Sequential Regioselective C-Arylation and N-Alkylation Enabled by SEM-Group Transposition

Natural Product Scaffolds as Leads to Drugs

Oocyte activation and passage through the metaphase/anaphase transition of the meiotic cell cycle is blocked in clams by inhibitors of HMG-CoA reductase activity.

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