Inhibitors of 2,3-Oxidosqualene-Lanosterol Cyclase as Antifungal Agents

Jolidon, Synèse; Polak-Wyss, A.; Hartman, P. G.; Guerry, Philippe

doi:10.1007/978-3-662-02740-0_9

Cited by 3 publications

(7 citation statements)

References 9 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Compounds inhibiting OSC from Candida albicans were tested on human OSC. Although there was no correlation between the IC 50 for human OSC and that for the fungal OSC, several of these compounds had motifs that were essential to the inhibition of both enzymes. , These are an amine function and an electrophilic carbonyl C atom embedded in a benzophenone system that are separated by about 10.7 Å. The best spacers between these two residues were either rigid benzyl or less rigid trans -butenyl or flexible alkyl chains.…”

Section: Biological Results and Discussionmentioning

confidence: 99%

“…In the absence of an X-ray structure of OSC, our approach for the design of new OSC inhibitors consisted of superimposing a prototype inhibitor on the high-energy intermediate of oxidosqualene 23,24 to optimize hydrophobic and ionic interactions with the transition state of the enzyme. The folded, high-energy intermediate of oxidosqualene cyclization was modeled as an opened protosterol, using the modeling program MOLOC.…”

Section: Introductionmentioning

confidence: 99%

“…The first compounds that represented a starting point for medicinal chemistry were found in the chemical collection of a fungicide project. , These compounds were further optimized to cholesterol-lowering agents such as Ro 48-8071 1 , active on mammalian OSC . A variety of OSC inhibitors have been published bearing amines, quinuclidines, isoquinolines, and a lipophilic residue.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Synthesis and Structure−Activity Studies of Novel Orally Active Non-Terpenoic 2,3-Oxidosqualene Cyclase Inhibitors

et al. 2003

View full text Add to dashboard Cite

New orally active non-terpenoic inhibitors of human 2,3-oxidosqualene cyclase (hOSC) are reported. The starting point for the optimization process was a set of compounds derived from a fungicide project, which in addition to showing high affinity for OSC from Candida albicans showed also high affinity for human OSC. Common structural elements of these inhibitors are an amine residue and an electrophilic carbonyl C atom embedded in a benzophenone system, which are at a distance of about 10.7 A. Considering that the keto moiety is in a potentially labile position, modifications of the substitution pattern at the benzophenone as well as annelated heteroaryl systems were explored. Our approach combined testing of the compounds first for increased binding affinity and for increased stability in vitro. Most promising compounds were then evaluated for their efficacy in lowering plasma total cholesterol (TC) and plasma low-density lipoprotein cholesterol (LDL-C) in hyperlipidemic hamsters. In this respect, the most promising compounds are the benzophenone derivative 1.fumarate and the benzo[d]isothiazol 24.fumarate, which lowered TC by 40% and 33%, respectively.

show abstract

Section: Biological Results and Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Synthesis and Structure−Activity Studies of Novel Orally Active Non-Terpenoic 2,3-Oxidosqualene Cyclase Inhibitors

et al. 2003

View full text Add to dashboard Cite

show abstract

“…The cyclization reactions of OSC and SHC involve the formation of several carbocations, among which the initial cation at one end of the hopenoid (and steroid) scaffold and the cation resulting from the last ring formation at the other end are suitable reference points. , Since the first cation emerges through protonation by an acid, it was thought that a positive charge provided by an inhibitor may form an ion pair with the respective acidic residue. The other carbocation arising from the last ring closure should then be around 12 Å away.…”

Section: Introductionmentioning

confidence: 99%

Binding Structures and Potencies of Oxidosqualene Cyclase Inhibitors with the Homologous Squalene−Hopene Cyclase

et al. 2003

View full text Add to dashboard Cite

The binding structures of 11 human oxidosqualene cyclase inhibitors designed as cholesterol-lowering agents were determined for the squalene-hopene cyclase from Alicyclobacillus acidocaldarius, which is the only structurally known homologue of the human enzyme. The complexes were produced by cocrystallization, and the structures were elucidated by X-ray diffraction analyses. All inhibitors were bound in the large active center cavity. The detailed binding structures are presented and discussed in the light of the IC50 values of these 11 as well as 17 other inhibitors. They provide a consistent picture for the inhibition of the bacterial enzyme and can be used to adjust and improve homology models of the human enzyme. The detailed active center structures of the two enzymes are too different to show an IC50 correlation.

show abstract

“…This solid was taken up in CH2Cl2, and the solution washed with H2O, brine and dried. The resultant solution was evaporated to dryness to yield an oil, which slowly crystallized to give, as a yellow solid, 28 (2.45 g, 90%): mp 131-132 °C; (14). 28 (0.411 g, 1.5 mmol) was dissolved in dry CH 2Cl2 (20 mL) and stirred at 0 °C.…”

Section: Example Of Synthetic Route a 1-(1-(4-pyridylmentioning

confidence: 99%

A Novel Series of 4-Piperidinopyridine and 4-Piperidinopyrimidine Inhibitors of 2,3-Oxidosqualene Cyclase−Lanosterol Synthase

et al. 2000

View full text Add to dashboard Cite

A novel series of 4-piperidinopyridines and 4-piperidinopyrimidines showed potent and selective inhibition of rat 2,3-oxidosqualene cyclase-lanosterol synthase (OSC) (e.g. 26 IC(50) rat = 398 +/- 25 nM, human = 112 +/- 25 nM) and gave selective oral inhibition of rat cholesterol biosynthesis (26 ED(80) = 1.2 +/- 0.3 mg/kg, n = 5; HMGCoA reductase inhibitor simvastatin ED(80) = 1.2 +/- 0.3 mg/kg, n = 5). The piperidinopyrimidine OSC inhibitors have a significantly lower pK(a) than the corresponding pyridine or the previously reported quinuclidine OSC inhibitor series. This indicates that other novel OSC inhibitors may be found in analogues of this series across a broader pK(a) range (6.0-9.0). These series may yield novel hypocholesterolemic agents for the treatment of cardiovascular disease.

show abstract

Inhibitors of 2,3-Oxidosqualene-Lanosterol Cyclase as Antifungal Agents

Cited by 3 publications

References 9 publications

Synthesis and Structure−Activity Studies of Novel Orally Active Non-Terpenoic 2,3-Oxidosqualene Cyclase Inhibitors

Synthesis and Structure−Activity Studies of Novel Orally Active Non-Terpenoic 2,3-Oxidosqualene Cyclase Inhibitors

Binding Structures and Potencies of Oxidosqualene Cyclase Inhibitors with the Homologous Squalene−Hopene Cyclase

A Novel Series of 4-Piperidinopyridine and 4-Piperidinopyrimidine Inhibitors of 2,3-Oxidosqualene Cyclase−Lanosterol Synthase

Contact Info

Product

Resources

About