Rapamycin (Sirolimus)

Rapamycin (Sirolimus)

(3S,6R,7E,9R,10R,12R,14S,15E,17E,19​E,21S,23S,26R,27R,34aS)-9,10,12,13,14,21,22,23,24,​25, 26,27,32,33,34,34a-Hexadecahydro-9,27-dihydroxy-3-​[(1R)-2-[(1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl]​-1-methylethyl]-10,21-dimethoxy-6,8,12,14,20,26-he​xamethyl-23,27-epoxy-3H-pyrido[2,1-c][1,4]oxaazacy​clohentriacontine-1,5,11,28,29(4H,6H,31H)-pentone

Wyeth Pharmaceuticals (Originator)

M.Wt:914.18

Formula:C₅₁H₇₉NO₁₃

53123-88-9 cas no

Antifungal and immunosuppressant. Specific inhibitor of mTOR (mammalian target of Rapamycin). Complexes with FKBP-12 and binds mTOR inhibiting its activity. Inhibits interleukin-2-induced phosphorylation and activation of p70 S6 kinase. Induces autophagy in yeast and mammalian cell lines.

Rapamycin is a triene macrolide antibiotic, which demonstrates anti-fungal, anti-inflammatory, anti-tumor and immunosuppressive properties. Rapamycin has been shown to block T-cell activation and proliferation, as well as, the activation of p70 S6 kinase and exhibits strong binding to FK-506 binding proteins. Rapamycin also inhibits the activity of the protein, mTOR, (mammalian target of rapamycin) which functions in a signaling pathway to promote tumor growth. Rapamycin binds to a receptor protein (FKBP12) and the rapamycin/FKB12 complex then binds to mTOR and prevents interaction of mTOR with target proteins in this signaling pathway. Rapamycin name is derived from the native word for Easter Island, Rapi Nui.

• (-)-Rapamycin
• Antibiotic AY 22989
• AY 22989
• AY-22989
• CCRIS 9024
• HSDB 7284
• NSC 226080
• Rapammune
• Rapamune
• Rapamycin
• SILA 9268A
• Sirolimus
• UNII-W36ZG6FT64
• WY-090217
• A 8167

A macrolide compound obtained from Streptomyces hygroscopicus that acts by selectively blocking the transcriptional activation of cytokines thereby inhibiting cytokine production. It is bioactive only when bound to IMMUNOPHILINS. Sirolimus is a potent immunosuppressant and possesses both antifungal and antineoplastic properties.

Sirolimus (INN/USAN), also known as rapamycin, is an immunosuppressant drug used to prevent rejection in organ transplantation; it is especially useful in kidney transplants. It prevents activation of T cells and B cells by inhibiting their response to interleukin-2 (IL-2). Sirolimus is also used as a coronary stent coating. Sirolimus works, in part, by eliminating old and abnormal white blood cells.^{[citation needed]} Sirolimus is effective in mice with autoimmunity and in children with a rare condition called autoimmune lymphoproliferative syndrome (ALPS).

sirolimus

A macrolide, sirolimus was discovered by Brazilian researchers as a product of the bacterium Streptomyces hygroscopicus in a soil sample fromEaster Island^[1] — an island also known as Rapa Nui.^[2] It was approved by the FDA in September 1999 and is marketed under the trade nameRapamune by Pfizer (formerly by Wyeth).

Sirolimus was originally developed as an antifungal agent. However, this use was abandoned when it was discovered to have potent immunosuppressive and antiproliferative properties. It has since been shown to prolong the life of mice and might also be useful in the treatment of certain cancers.

Unlike the similarly named tacrolimus, sirolimus is not a calcineurin inhibitor, but it has a similar suppressive effect on the immune system. Sirolimus inhibits the response tointerleukin-2 (IL-2), and thereby blocks activation of T and B cells. In contrast, tacrolimus inhibits the secretion of IL-2.

The mode of action of sirolimus is to bind the cytosolic protein FK-binding protein 12(FKBP12) in a manner similar to tacrolimus. Unlike the tacrolimus-FKBP12 complex which inhibits calcineurin (PP2B), the sirolimus-FKBP12 complex inhibits themammalian target of rapamycin (mTOR, rapamycin being an older name for sirolimus) pathway by directly binding the mTOR Complex1 (mTORC1).

mTOR has also been called FRAP (FKBP-rapamycin associated protein), RAFT (rapamycin and FKBP target), RAPT1, or SEP. The earlier names FRAP and RAFT were coined to reflect the fact that sirolimus must bind FKBP12 first, and only the FKBP12-sirolimus complex can bind mTOR. However, mTOR is now the widely accepted name, since Tor was first discovered via genetic and molecular studies of sirolimus-resistant mutants of Saccharomyces cerevisiae that identified FKBP12, Tor1, and Tor2 as the targets of sirolimus and provided robust support that the FKBP12-sirolimus complex binds to and inhibits Tor1 and Tor2.

rapamycin

Unlike the similarly named tacrolimus, sirolimus is not a calcineurin inhibitor, but it has a similar suppressive effect on the immune system. Sirolimus inhibits the response to interleukin-2 (IL-2), and thereby blocks activation of T and B cells. In contrast, tacrolimus inhibits the secretion of IL-2.

The mode of action of sirolimus is to bind the cytosolic protein FK-binding protein 12 (FKBP12) in a manner similar to tacrolimus. Unlike the tacrolimus-FKBP12 complex which inhibits calcineurin (PP2B), the sirolimus-FKBP12 complex inhibits the mammalian target of rapamycin(mTOR, rapamycin being an older name for sirolimus) pathway by directly binding the mTOR Complex1 (mTORC1).

mTOR has also been called FRAP (FKBP-rapamycin associated protein), RAFT (rapamycin and FKBP target), RAPT1, or SEP. The earlier names FRAP and RAFT were coined to reflect the fact that sirolimus must bind FKBP12 first, and only the FKBP12-sirolimus complex can bind mTOR. However, mTOR is now the widely accepted name, since Tor was first discovered via genetic and molecular studies of sirolimus-resistant mutants of Saccharomyces cerevisiae that identified FKBP12, Tor1, and Tor2 as the targets of sirolimus and provided robust support that the FKBP12-sirolimus complex binds to and inhibits Tor1 and Tor2.

SIROLIMUS

Rapamycin and its preparation are described in US Patent No. 3,929,992, issued December 30, 1975. Alternatively, rapamycin may be purchased commercially [Rapamune®, Wyeth].

Rapamycin (Sirolimus) is a 31-member natural macrocyclic lactone [C51H79N1O13; MWt=914.2] produced by Streptomyces hygroscopicus and found in the 1970s (U.S. Pat. No. 3,929,992; 3,993,749). Rapamycin (structure shown below) was approved by the Food and Drug Administration (FDA) for the prophylaxis of renal transplant rejection in 1999.

Rapamycin resembles tacrolimus (binds to the same intracellular binding protein or immunophilin known as FKBP-12) but differs in its mechanism of action. Whereas tacrolimus and cyclosporine inhibit T-cell activation by blocking lymphokine (e.g., IL2) gene transcription, sirolimus inhibits T-cell activation and T lymphocyte proliferation by binding to mammalian target of rapamycin (mTOR). Rapamycin can act in synergy with cyclosporine or tacrolimus in suppressing the immune system.

Rapamycin is also useful in preventing or treating systemic lupus erythematosus [U.S. Pat. No. 5,078,999], pulmonary inflammation [U.S. Pat. No. 5,080,899], insulin dependent diabetes mellitus [U.S. Pat. No. 5,321,009], skin disorders, such as psoriasis [U.S. Pat. No. 5,286,730], bowel disorders [U.S. Pat. No. 5,286,731], smooth muscle cell proliferation and intimal thickening following vascular injury [U.S. Pat. Nos. 5,288,711 and 5,516,781], adult T-cell leukemia/lymphoma [European Patent Application 525,960 A1], ocular inflammation [U.S. Pat. No. 5,387,589], malignant carcinomas [U.S. Pat. No. 5,206,018], cardiac inflammatory disease [U.S. Pat. No. 5,496,832], anemia [U.S. Pat. No. 5,561,138] and increase neurite outgrowth [Parker, E. M. et al, Neuropharmacology 39, 1913-1919, 2000].

Although rapamycin can be used to treat various disease conditions, the utility of the compound as a pharmaceutical drug has been limited by its very low and variable bioavailability and its high immunosuppressive potency and potential high toxicity. Also, rapamycin is only very slightly soluble in water. To overcome these problems, prodrugs and analogues of the compound have been synthesized. Water soluble prodrugs prepared by derivatizing rapamycin positions 31 and 42 (formerly positions 28 and 40) of the rapamycin structure to form glycinate, propionate, and pyrrolidino butyrate prodrugs have been described (U.S. Pat. No. 4,650,803). Some of the analogues of rapamycin described in the art include monoacyl and diacyl analogues (U.S. Pat. No. 4,316,885), acetal analogues (U.S. Pat. No. 5,151,413), silyl ethers (U.S. Pat. No. 5,120,842), hydroxyesters (U.S. Pat. No. 5,362,718), as well as alkyl, aryl, alkenyl, and alkynyl analogues (U.S. Pat. Nos. 5,665,772; 5,258,389; 6,384,046; WO 97/35575).

.................................................

Synthesis

http://www.google.co.in/patents/US3929992

PREPARATION

CUT PASTE FROM TEXT

In one embodiment of this invention rapamycin is prepared in the followingmanner: 4

A suitable fermenter is charged with production meis reached in the fermentation mixture after 2-8 days,

usually after about 5 days, as determined by the cup plate method and Candida albicans as the test organism. The mycelium is harvested by filtration with diatomaceous earth. Rapamycin is then extracted from the mycelium with a water-miscible solvent, for example a lower alkanol, preferably methanol or ethanol. The latter extract is then concentrated, preferably under reduced pressure, and the resulting aqueous phase is extracted with a water-immiscible solvent. A preferred water-immiscible solvent for this purpose is methylene dichloride although chloroform, carbon tetrachloride, benzene, n-butanol and the like may also be used. The latter extract is concentrated, preferably under reduced pressure, to afford the crude product as an oil.

The product may be purified further by a variety of methods. Among the preferred methods of purification is to dissolve the crude product in a substantially nonpolar, first solvent, for example petroleum ether or hexane, and to treat the resulting solution with a suit able absorbent, for example charcoal or silica gel, so that the antibiotic becomes absorbed on the absorbant. The absorbant is then separated and washed or eluted with a second solvent more polar than the first solvent, for example ethyl acetate, methylene dichloride, or a mixture of methylene dichloride and ether (preferred). Thereafter, concentration of the wash solution or eluate affords substantially pure rapamycin. Further purification is obtained by partial precipitation with a nonpolar solvent, for example, petroleum ether, hexane, pentane and the like, from a solution of the rapamycin in a more polar solvent, for example, ether, ethyl acetate, benzene and the like. Still-further purification is obtained by column chromatography, preferably employing silica gel, and by crystallization of the rapamycin from ether.

In another preferred embodiment of this invention a first stage inoculum of S treptomyces hygroscopicus NRRL 5491 is prepared in small batches in a medium containing soybean flour, glucose, ammonium sulfate, and calcium carbonate incubated at about 25C at pH 7.l-7.3 for 24 hrs. with agitation, preferably on a gyrotary shaker. The growth thus obtained is used to inoculate a number of somewhat larger batches of the same medium as described above which are incubated at about 25C and pH 7.1-7.3 for 18 hrs. with agitation, preferably on a reciprocating'shaker, to obtain a sec- "ond stagc inoculum which is used to inoculate the production stage fermenters.

6 5.86'.2.-The fermenters are inoculated with the second stage inoculum described above and incubated at about 25C with' agitationand aeration while controlling and 'mai'ntaining the mixture at approximately pH 6.0 by

addition offa base, for example, sodium hydroxide, potassium hydroxide or preferably ammonium hydroxide, as required from time to time. Addition of a source -of assimilable carbon, preferably glucose, is started when theconcentrationof the latter in the broth has dropped to about 0.5% wt/vol, normally about 48 hrs after. the start of fermentation, and is maintained until the end ofthe particular run. In this manner a fermentation broth containing about 60 ug/ml of rapamycin as determined by the assay method described above is obtained in 45 days, when fermentation is stopped.

' Filtration of the'mycelium, mixing the latter with a watef-miscible 'lower' alkanol, preferably methanol, followed by extraction with a halogenated aliphatic hydrocarbon, preferably trichloroethane, and evaporation of the solvents yields a first oily residue. This first oily residue is dissolved in a lower aliphatic ketone, preferably acetone, filtered from insoluble impurities, the filtrate evaporated to yield a second oily residue which is extractedjwith a water-miscible lower alkanol,

preferably methanol, and the latter extract is evaporated to yield crude rapamycin as a third oily residue. This third oily residue is dissolved in a mixture of a lower aliphatic ketone and a lower aliphatic hydrocarbon, preferably acetone-hexane, an absorbent such as charcoal or preferably silica gel is added to adsorb the rapamycin, the latter is eluted from the adsorbate with a similar but more polar solvent mixture, for example a mixture as above but containing a higher proportion of the aliphatic ketone, the eluates are evaporated and the residue is crystallized from diethyl ether, to yield pure crystalline rapamycin. In this manner a total of 45-5 8% of the rapamycin initially present in the fermentation mixture is recovered as pure crystalline rapamycin.

CHARACTERIZATION solvent systems; for example, ether-hexane 40:60 (Rf 0.42), 'isopropyl alcoholvbenzene 15:85 (Rf= 0.5) and ethanol-benzene 20:80 (Rf f 0.43);

d. rapamycin obtained from four successive fermentation batchesgave the following values on repeated The production stage fermenters are equipped with 7 devices for controlling and maintaining pH at a predetermined level and for continuous metered addition of elemental analyses:

AVER- e. rapamycin exhibits the following characteristic absorption maxima in its ultraviolet absorption spectrum ethanol):

f. the infrared absorption spectrum of rapamycin in chloroform is reproduced in FIG. 1 and shows characteristic absorption bands at 3560, 3430, 1730, 1705 and 1630-1610 cm;

Further infrared absorption bands are characterized by the following data given in reciprocal centimeters with (s) denoting a strong, (m) denoting a medium, and (w) denoting a weak intensity band. This classification is arbitrarily selected in such a manner that a band is denoted as strong (s) if its peak absorption is more than two-thirds of the background in the same region; medium (m) if its peak is between one-third and twothirds of the background in the same region; and weak (w) if its peak is less than one-third of the background in the same region.

2990 cm (m) 1158 cm" (m) 2955 cm (s) 1129 cm (s) 2919 cm (s) 1080 cm (s) 2858 cm (s) 1060 cm (s) 2815 cm (m) 1040 cm (m) 1440 cm (s) 1020 crn' (m) 1365 cm (m) 978 cm" (s) 1316 cm (in) 905 cm (m) 1272 cm (m) 888 cm" (w) 1178 cm (s) 866 cm- (w) g. the nuclear magnetic resonance spectrum of rapamycinin deuterochloroform is reproduced in FIG. 2; SEE PATENT

CLAIMS

l. Rapamycin, an antibiotic which a. is a colourless, crystalline compound with a melting point of 183 to l8SC, after recrystallization from ether;

b. is soluble in ether, chloroform, acetone, methanol and dimethylformamide, very sparingly soluble in hexane and petroleum ether and substantially insoluble in water;

c. shows a uniform spot on thin layer plates of silica gel",

d. has a characteristic elemental analysis of about C,

e. exhibits the following characteristic absorption maxima in its ultraviolet absorption spectrum (95% ff has 'a characteristic infrared absorption spectrum shown in accompanying FIG. 1; SEE PATENT

.....................................................

Rapamycin synthetic studies. 1. Construction of the C(27)-C(42) subunit. Tetrahedron Lett 1994, 35, 28, 4907

A partial synthesis of rapamycin has been reported: The condensation of sulfone (I) with epoxide (II) by means of butyllithium followed by desulfonation with Na/Hg gives the partially protected diol (III), which is treated with methanesulfonyl chloride and NaH to afford the epoxide (IV). Ring opening of epoxide (IV) with LiI and BF3.Et2O followed by protection of the resulting alcohol with PMBOC(NH)CCl3 yields the primary iodo compound (V). The condensation of (V) with the fully protected dihydroxyaldehyde (VI) (see later) by means of butyllithium in THF/HMPT gives the fully protected trihydroxyketone (VII), which is hydrolyzed with camphorsulfonic acid (CSA) to the corresponding gemdiol and reprotected with pivaloyl chloride (the primary alcohol) and tert-butyldimethylsilyl trifluoromethanesulfonate (the secondary alcohol), yielding a new fully protected trihydroxyketone (VIII). Elimination of the pivaloyl group with DIBAL and the dithiane group with MeI/CaCO3 affords the hydroxyketone (IX), which is finally oxidized with oxalyl chloride to the ketoaldehyde (X), the C(27)-C(42) fragment [the C(12)-C(15) fragment with the C(12)-substituent based on the IUPAC nomenclature recommendations]. The fully protected dihydroxyaldehyde (VI) is obtained as follows: The reaction of methyl 3-hydroxy-2(R)-methylpropionate (XI) with BPSCl followed by reduction with LiBH4 to the corresponding alcohol and oxidation with oxalyl chloride gives the aldehyde (XII), which is protected with propane-1,3-dithiol and BF3.Et2O to afford the dithiane compound (XIII). Elimination of the silyl group with TBAF followed by esterification with tosyl chloride, reaction with NaI and, finally, with sodium phenylsulfinate gives the sulfone (XIV), which is condensed with the partially protected dihydroxyaldehyde (XV), oxidized with oxalyl chloride and desulfonated with Al/Hg to afford the dithianyl ketone (XVI). The reaction of (XVI) with lithium hexamethyldisilylazane gives the corresponding enolate, which is treated with dimethyllithium cuprate to yield the fully protected unsaturated dihydroxyaldehyde (VI).

...................................................

http://www.google.com/patents/US8088789

.................................

The Ley Synthesis of Rapamycin Rapamycin (3) is used clinically as an immunosuppressive agent. The synthesis of 3 (Angew. Chem. Int. Ed. 2007, 46, 591. DOI: 10.1002/anie.200604053) by Steven V. Ley of the University of Cambridge was based on the assembly and subsequent coupling of the iododiene 1 and the stannyl alkene 2. The lactone of 1 was prepared by Fe-mediated cyclocarbonylation of the alkenyl epoxide 5, following the protocol developed in the Ley group. The cyclohexane of 2 was constructed by SnCl4-mediated cyclization of the allyl stannane 9, again employing a procedure developed in the Ley group. Hydroboration delivered the aldehyde 11, which was crotylated with 12, following the H. C. Brown method. The alcohol so produced (not illustrated) was used to direct the diastereoselectivity of epoxidation, then removed, to give 13. Coupling with 14 then led to 2. Combination of 1 with 2 led to 15, which was condensed with catechol to give the macrocycle 16. Exposure of 16 to base effected Dieckmann cyclization, to deliver the ring-contracted macrolactone 17, which was carried on to (-)-rapamycin (3).

.....................................

Total Synthesis of Rapamycin

Angewandte Chemie International Edition

Volume 46, Issue 4, pages 591–597, January 15, 2007

PREVIEW THIS ARTICLE WITH READCUBE

http://www.readcube.com/articles/10.1002%2Fanie.200604053?r3_referer=wol

..........................

Ley, Maddess, Tackett, Watanabe, Brennan, Spilling, Scott and Osborn. ACIEE, 2006, EarlyView. DOI:10.1002/anie.200604053.

It’s been in the works for quite a while, but Steve Ley’s synthesis of Rapamycin has just been published. This complex beast has a multitude of biological activities, including an interesting immunosuppressive profile, resulting in clinical usage following organ transplantation. So, unsurprisingly, it’s been the target of many projects, with complete total syntheses published by Smith, Danishefsky, Schreiber and KCN.

So what makes this one different? Well, it does have one of the most interesting macrocyclisations I’ve seen since Jamison’s paper, and a very nice demonstration of the BDA-aldol methodology. The overall strategy is also impressive, so on with the retro:

First stop is the BDA-aldol; this type of chemistry is interesting, because the protecting group for the diol is also the stereo-directing group. The stereochemistry for this comes from a glycolic acid, and has been usedin this manner by the group before. The result is as impressive as ever, with a high yield, and presumably a very high d.r. (no mention of actual numbers).

The rest of the fragment synthesis was completed in a succinct and competent manner, but using relatively well known chemistry. However, I was especially impressed with the macrocyclisation I mentioned:

Tethering the free ends of the linear precursor with a simple etherification/esterification onto catechol gave then a macrocycle holding the desired reaction centres together. Treatment of this with base then induces a Dieckmann-condensation type cyclisation to deliver the desired macrocycle. Of course, at this stage, only a few more steps were required to complete the molecule, and end an era of the Wiffen Lab.

....................................

Drugs Fut 1999, 24(1): 22

DOI: 10.1358/dof.1999.024.01.474036

REFERENCES

1.  Vézina C, Kudelski A, Sehgal SN (October 1975). "Rapamycin (AY-22,989), a new antifungal antibiotic". J. Antibiot. 28 (10): 721–6. doi:10.7164/antibiotics.28.721. PMID 1102508.
2. Pritchard DI (2005). "Sourcing a chemical succession for cyclosporin from parasites and human pathogens". Drug Discovery Today 10 (10): 688–691. doi:10.1016/S1359-6446(05)03395-7. PMID 15896681.

3. Creating diverse target-binding surfaces on FKBP12: synthesis and evaluation of a rapamycin analogue library.

Wu X, Wang L, Han Y, Regan N, Li PK, Villalona MA, Hu X, Briesewitz R, Pei D.
ACS Comb Sci. 2011 Sep 12;13(5):486-95. doi: 10.1021/co200057n. Epub 2011 Jul 28.

4. Mammalian target of rapamycin: discovery of rapamycin reveals a signaling pathway important for normal and cancer cell growth.

Gibbons JJ, Abraham RT, Yu K.
Semin Oncol. 2009 Dec;36 Suppl 3:S3-S17. doi: 10.1053/j.seminoncol.2009.10.011. Review.

5. Hybrid inhibitors of phosphatidylinositol 3-kinase (PI3K) and the mammalian target of rapamycin (mTOR): design, synthesis, and superior antitumor activity of novel wortmannin-rapamycin conjugates.

Ayral-Kaloustian S, Gu J, Lucas J, Cinque M, Gaydos C, Zask A, Chaudhary I, Wang J, Di L, Young M, Ruppen M, Mansour TS, Gibbons JJ, Yu K.
J Med Chem. 2010 Jan 14;53(1):452-9. doi: 10.1021/jm901427g.

6. Fluorescent probes to characterise FK506-binding proteins.

Kozany C, März A, Kress C, Hausch F.
Chembiochem. 2009 May 25;10(8):1402-10. doi: 10.1002/cbic.200800806.

7. Recent advances in the chemistry, biosynthesis and pharmacology of rapamycin analogs.

Graziani EI.
Nat Prod Rep. 2009 May;26(5):602-9. doi: 10.1039/b804602f. Epub 2009 Mar 5. Review.

8 Total synthesis of rapamycin.

Ley SV, Tackett MN, Maddess ML, Anderson JC, Brennan PE, Cappi MW, Heer JP, Helgen C, Kori M, Kouklovsky C, Marsden SP, Norman J, Osborn DP, Palomero MA, Pavey JB, Pinel C, Robinson LA, Schnaubelt J, Scott JS, Spilling CD, Watanabe H, Wesson KE, Willis MC.
Chemistry. 2009;15(12):2874-914. doi: 10.1002/chem.200801656.

9  Highly diastereoselective desymmetrisation of cyclic meso-anhydrides and derivatisation for use in natural product synthesis.

Evans AC, Longbottom DA, Matsuoka M, Davies JE, Turner R, Franckevicius V, Ley SV.
Org Biomol Chem. 2009 Feb 21;7(4):747-60. doi: 10.1039/b813494d. Epub 2009 Jan 6.

10  Total synthesis studies on macrocyclic pipecolic acid natural products: FK506, the antascomicins and rapamycin.

Maddess ML, Tackett MN, Ley SV.
Prog Drug Res. 2008;66:13, 15-186. Review.

11 Determination of sirolimus in rabbit arteries using liquid chromatography separation and tandem mass spectrometric detection.

Zhang J, Rodila R, Watson P, Ji Q, El-Shourbagy TA.
Biomed Chromatogr. 2007 Oct;21(10):1036-44.

12  Saccharomyces cerevisiae FKBP12 binds Arabidopsis thaliana TOR and its expression in plants leads to rapamycin susceptibility.

Sormani R, Yao L, Menand B, Ennar N, Lecampion C, Meyer C, Robaglia C.
BMC Plant Biol. 2007 Jun 1;7:26.

13 Total synthesis of rapamycin.

Maddess ML, Tackett MN, Watanabe H, Brennan PE, Spilling CD, Scott JS, Osborn DP, Ley SV.
Angew Chem Int Ed Engl. 2007;46(4):591-7. No abstract available.

14 Drug evaluation: AP-23573--an mTOR inhibitor for the treatment of cancer.

Elit L.
IDrugs. 2006 Sep;9(9):636-44.

 

15 lipase-catalyzed regioselective esterification of rapamycin: synthesis of temsirolimus (CCI-779).

Gu J, Ruppen ME, Cai P.
Org Lett. 2005 Sep 1;7(18):3945-8.

16 CCI-779 Wyeth.

Elit L.
Curr Opin Investig Drugs. 2002 Aug;3(8):1249-53. Review.

17 Everolimus. Novartis.

Dumont FJ.
Curr Opin Investig Drugs. 2001 Sep;2(9):1220-34. Review.

18 Kuo et al (1992) Rapamycin selectively inhibits interleukin-2 activation of p70 S6 kinase. Nature 358 70. PMID:1614535.

19 Huang et al (2003) Rapamycins: mechanism of action and cellular resistance. Cancer Biol.Ther. 2 221. PMID:12878853.

20 Kobayashi et al (2007) Rapamycin, a specific inhibitor of the mammalian target of rapamycin, suppresses lymphangiogenesis and lymphatic metastasis. Cancer Sci. 98 726. PMID: 17425689.

21 Fleming et al (2011) Chemical modulators of autophagy as biological probes and potential therapeutics. 7 9. PMID:21164513.

22 J Am Chem Soc1993,115,(10):4419

23 Tetrahedron Lett1994,35,(28):4911
24 Chemistry (Weinheim)1995,1,(5):318

24
SIROLIMUS

FEMALE FERTILITY
http://amcrasto.theeurekamoments.com/2013/02/11/immunosuppressant-drug-rapamycin-helps-preserving-female-fertility/

PATENTS

Canada	2293793	APPROVED2006-07-11	EXP    2018-06-11
Canada	2103571	2003-04-29	2012-02-21
United States	5989591	1998-09-11	2018-09-11
United States	5212155	1993-05-18	2010-05-18

WO1998054308A2 *	May 28, 1998	Dec 3, 1998	Biotica Tech Ltd	Polyketides and their synthesis and use
EP0589703A1 *	Sep 23, 1993	Mar 30, 1994	American Home Products Corporation	Proline derivative of rapamycin, production and application thereof
US20010039338 *	Jun 7, 2001	Nov 8, 2001	American Home Products Corporation	Regioselective synthesis of rapamycin derivatives

WO2007067560A2 *	Dec 6, 2006	Jun 14, 2007	Clifford William Coughlin	Scalable process for the preparation of a rapamycin 42-ester from a rapamycin 42-ester boronate
WO2012131019A1	Mar 30, 2012	Oct 4, 2012	Sandoz Ag	Regioselective acylation of rapamycin at the c-42 position
US7622578	Dec 6, 2006	Nov 24, 2009	Wyeth	Scalable process for the preparation of a rapamycin 42-ester from a rapamycin 42-ester boronate

US3929992	Apr 12, 1974	Dec 30, 1975	Ayerst Mckenna & Harrison	Rapamycin and process of preparation
US5646160	May 26, 1995	Jul 8, 1997	American Home Products Corporation	Method of treating hyperproliferative vascular disease with rapamycin and mycophenolic acid
US5665772	Sep 24, 1993	Sep 9, 1997	Sandoz Ltd.	O-alkylated rapamycin derivatives and their use, particularly as immunosuppressants
US5728710	Jul 16, 1993	Mar 17, 1998	Smithkline Beecham Corporation	Rapamycin derivatives
US5957975	Dec 15, 1997	Sep 28, 1999	The Centre National De La Recherche Scientifique	Stent having a programmed pattern of in vivo degradation
US5985890	Jun 5, 1996	Nov 16, 1999	Novartis Ag	Rapamycin derivatives
US6001998	Oct 13, 1995	Dec 14, 1999	Pfizer Inc	Macrocyclic lactone compounds and their production process
US6015815	Sep 24, 1998	Jan 18, 2000	Abbott Laboratories	Tetrazole-containing rapamycin analogs with shortened half-lives
US6187568	Aug 20, 1999	Feb 13, 2001	Pfizer Inc	Macrocyclic lactone compounds and their production process
US6273913	Apr 16, 1998	Aug 14, 2001	Cordis Corporation	Modified stent useful for delivery of drugs along stent strut
US6585764	Jun 4, 2001	Jul 1, 2003	Cordis Corporation	Stent with therapeutically active dosage of rapamycin coated thereon
US6641611	Nov 26, 2001	Nov 4, 2003	Swaminathan Jayaraman	Therapeutic coating for an intravascular implant
US6805703	Sep 18, 2001	Oct 19, 2004	Scimed Life Systems, Inc.	Protective membrane for reconfiguring a workpiece
US7025734	Sep 28, 2001	Apr 11, 2006	Advanced Cardiovascular Systmes, Inc.	Guidewire with chemical sensing capabilities
US7056942	Jan 16, 2004	Jun 6, 2006	Teva Pharmaceutical Industries Ltd.	Carvedilol
US7820812 *	Jul 23, 2007	Oct 26, 2010	Abbott Laboratories	Methods of manufacturing crystalline forms of rapamycin analogs
US20010027340	Jun 4, 2001	Oct 4, 2001	Carol Wright	Stent with therapeutically active dosage of rapamycin coated thereon
US20010029351	May 7, 2001	Oct 11, 2001	Robert Falotico	Drug combinations and delivery devices for the prevention and treatment of vascular disease
US20020005206	May 7, 2001	Jan 17, 2002	Robert Falotico	Antiproliferative drug and delivery device
US20020007213	May 7, 2001	Jan 17, 2002	Robert Falotico	Drug/drug delivery systems for the prevention and treatment of vascular disease
US20020082680	Sep 7, 2001	Jun 27, 2002	Shanley John F.	Expandable medical device for delivery of beneficial agent
US20020123505	Sep 10, 2001	Sep 5, 2002	Mollison Karl W.	Medical devices containing rapamycin analogs
US20030129215	Sep 6, 2002	Jul 10, 2003	T-Ram, Inc.	Medical devices containing rapamycin analogs
US20040072857	Jul 2, 2003	Apr 15, 2004	Jacob Waugh	Polymerized and modified rapamycins and their use in coating medical prostheses
US20050033417	Jul 1, 2004	Feb 10, 2005	John Borges	Coating for controlled release of a therapeutic agent
US20050101624	Nov 12, 2003	May 12, 2005	Betts Ronald E.	42-O-alkoxyalkyl rapamycin derivatives and compositions comprising same
US20050152842	Dec 22, 2004	Jul 14, 2005	Chun Li	Poly (L-glutamic acid) paramagnetic material complex and use as a biodegradable MRI contrast agent
US20050175660	Oct 29, 2004	Aug 11, 2005	Mollison Karl W.	Medical devices containing rapamycin analogs
US20050208095	Nov 22, 2004	Sep 22, 2005	Angiotech International Ag	Polymer compositions and methods for their use
US20050209244	Feb 27, 2003	Sep 22, 2005	Prescott Margaret F	N{5-[4-(4-methyl-piperazino-methyl)-benzoylamido]-2-methylphenyl}-4-(3-pyridyl)-2-pyrimidine-amine coated stents
US20050239178	Apr 25, 2005	Oct 27, 2005	Wyeth	Labeling of rapamycin using rapamycin-specific methylases
US20060094744	Sep 28, 2005	May 4, 2006	Maryanoff Cynthia A	Pharmaceutical dosage forms of stable amorphous rapamycin like compounds
US20060229711	Apr 4, 2006	Oct 12, 2006	Elixir Medical Corporation	Degradable implantable medical devices
US20070015697	Nov 1, 2005	Jan 18, 2007	Peyman Gholam A	Enhanced ocular neuroprotection and neurostimulation
US20070059336	Feb 27, 2006	Mar 15, 2007	Allergan, Inc.	Anti-angiogenic sustained release intraocular implants and related methods
US20070207186	Mar 3, 2007	Sep 6, 2007	Scanlon John J	Tear and abrasion resistant expanded material and reinforcement
US20080086198	May 24, 2007	Apr 10, 2008	Gary Owens	Nanoporous stents with enhanced cellular adhesion and reduced neointimal formation
EP1236478A1	Feb 27, 2002	Sep 4, 2002	Medtronic Ave, Inc.	Peroxisome proliferator-activated receptor gamma ligand eluting medical device
EP1588727A1	Apr 20, 2005	Oct 26, 2005	Cordis Corporation	Drug/drug delivery systems for the prevention and treatment of vascular disease
WO1993016189A1	Feb 11, 1993	Aug 19, 1993	Pfizer	Novel macrocyclic lactones and a productive strain thereof
WO1994009010A1	Sep 24, 1993	Apr 28, 1994	Sandoz Ag	O-alkylated rapamycin derivatives and their use, particularly as immunosuppressants
WO1996041807A1	Jun 5, 1996	Dec 27, 1996	Sylvain Cottens	Rapamycin derivatives
WO1998007415A2	Aug 18, 1997	Feb 26, 1998	Ciba Geigy Ag	Methods for prevention of cellular proliferation and restenosis
WO2001087263A2	May 14, 2001	Nov 22, 2001	Cordis Corp	Delivery systems for treatment of vascular disease
WO2001087342A2	May 14, 2001	Nov 22, 2001	Cordis Corp	Delivery devices for treatment of vascular disease
WO2001087372A1	Apr 25, 2001	Nov 22, 2001	Cordis Corp	Drug combinations useful for prevention of restenosis
WO2001087373A1	May 14, 2001	Nov 22, 2001	Cordis Corp	Delivery devices for treatment of vascular disease
WO2001087374A1	May 14, 2001	Nov 22, 2001	Cordis Corp	Delivery systems for treatment of vascular disease
WO2001087375A1	May 14, 2001	Nov 22, 2001	Cordis Corp	Delivery devices for treatment of vascular disease
WO2001087376A1	May 14, 2001	Nov 22, 2001	Cordis Corp	Drug/drug delivery systems for the prevention and treatment of vascular disease
WO2002056790A2	Dec 18, 2001	Jul 25, 2002	Avantec Vascular Corp	Delivery of therapeutic capable agents
WO2002065947A2	Feb 18, 2002	Aug 29, 2002	Jomed Gmbh	Implants with fk506 for prophylaxis and treatment of restonoses
WO2003064383A2	Feb 3, 2003	Aug 7, 2003	Ariad Gene Therapeutics Inc	Phosphorus-containing compounds & uses thereof
WO2006116716A2	Apr 27, 2006	Nov 2, 2006	William A Dunn	Materials and methods for enhanced degradation of mutant proteins associated with human disease

A plaque, written in Brazilian Portuguese, commemorating the discovery of sirolimus on Easter Island, near Rano Kau

mTOR inhibitor
temsirolimus (CCI-779), everolimus (RAD001), deforolimus (AP23573), AP21967, biolimus, AP23102, zotarolimus (ABT 578), sirolimus (Rapamune), and tacrolimus (Prograf).