137071-32-0 Usage
Description
Pimecrolimus is an ascomycin macrolactam derivative, developed as a topical formulation (1% cream) for the treatment of mild to moderate atopic dermatitis for patients aged two years and over in whom the use of conventional therapies is inadvisable. Pimecrolimus is an inflammatory cytokine inhibitor that works by selectively targeting T-cells in the skin. It inhibits in vitro the production and release of pro-inflammatory cytokines after antigen-specific or non-specific stimulation in T cells and mast cells. Pimecrolimus binds specifically to cytosolic receptor macrophilin-12 at nanomolar concentrations leading to inhibition of the Ca2+/calmodulin-dependent phosphatase, calcineurin.
Uses
Used in Pharmaceutical Industry:
Pimecrolimus is used as an immunosuppressant for the treatment of inflammatory skin disorders. It selectively blocks the production and release of cytokines from T-cells, which cause inflammation, redness, and itching associated with eczema. Long-term therapy with pimecrolimus was more effective than conventional treatment in reducing the incidence of disease flares and the use of corticosteroids.
Used in Pediatric Dermatology:
Pimecrolimus is used as a non-steroid agent for the treatment of mild to moderate atopic dermatitis in pediatric patients. It is safe and effective in children as young as two years and does not cause skin atrophy, unlike corticosteroids.
Used in Topical Dermatological Treatments:
Pimecrolimus is used as a topical treatment for atopic dermatitis, providing an alternative to conventional corticosteroids. It has demonstrated greater efficiency in reducing the incidence of disease flares and the use of second-line corticosteroids in both adults and pediatric patients.
Used in Research and Development:
Pimecrolimus is used as a research compound for studying the effects of inflammatory cytokine inhibition on various skin conditions and for the development of new treatments for inflammatory skin disorders.
Chemical Properties:
Pimecrolimus is a white solid.
Brand Name:
Elidel (Novartis).
Topical immunomodulators
Pimecrolimus is a topical immunomodulators and is a kind of semi-synthetic products of the Streptomyces-produced ascomycin. It has a greater lipophilicity than tacrolimus with a stronger affinity with the skin. It can effectively and safely control the signs and symptoms of facial seborrheic dermatitis and can quickly relieve the itching symptoms of patients with dermatitis and eczema as well as reduce the lesion area, clear atopic dermatitis (eczema) sign. Therefore, it is an effective treatment method for the treatment of atopic dermatitis (eczema) for both early remission purpose and long-term control purpose.
Seborrheic dermatitis is the body's immune inflammatory response to lipophilic Malassezia. Both the humoral and cellular immunity participate in the sickening process. Pimecrolimus can selectively inhibit the activation of T cell through inhibiting the activity of the calcium-dependent nerve transcription proteins which is indispensible for the activation of T cells and prevent the release of cytokines and pro-inflammatory mediator, and further exhibiting strong anti-inflammatory activity. These results suggest that the mechanism of pimecrolimus for treatment of seborrheic dermatitis comes from its anti-inflammatory effect and immune regulation. Currently there have been no reports regarding on its direct participation of antifungal activity. But in recent years, there have been reports finding that tacrolimus (a kind of immunomodulatory agents with similar chemical structure and mechanisms as pimecrolimus) have some anti-Malassezia activity.
Similar as the tacrolimus, pimecrolimus is a cellular selective inhibitor which is produced and released by the pro-inflammatory cytokine and can combine with macrophilin 12 (FKBP-12) to inhibit of calcium-dependent calcineurin as well as suppress the T-cell activation through blocking the early cytokines transcription of T cells. In particular, a level of nanogram is enough to suppress the synthesis of T cell IL-2 and IFN-γ (Th1 cell origin) factor and can also inhibit the synthesis of IL-4 and IL (Th2 cell-derived). In addition, in vitro experiments, pimecrolimus can also be applied to inhibit the antigen as well as IgE stimulated mast cells’ release of inflammatory cytokines and inflammatory mediators [4, 5]. Clinical data have shown that after topical application, the blood concentration is very low and is usually under the detected value (<0.5 ng/mL). It also has no drug accumulation phenomenon.
The above information is edited by the lookchem of Dai Xiongfeng.
Originator
Novartis (USA)
Indications
Pimecrolimus (SDZ ASM 981, Elidel) is another recently
approved macrolide immunosuppressant that
acts by inhibiting calcineurin and blocking the release
of proinflammatory cytokines from T lymphocytes. The
parent compound, ascomycin, was originally isolated
from Streptomyces hygroscopicus var ascomyceticus.
Like tacrolimus, pimecrolimus is approved for the topical
treatment of moderate to severe atopic dermatitis
that is refractory to other therapies.Transient local irritation
is a common side effect.
Synthesis
The syntheses of
pimecrolimus (21) appeared in several patent applications. Starting material 178 was prepared by either
fermentation or modification of a previously described
synthetic method in the literature. Treatment of macrolide 178 with triisopropylsilyl trifluoromethanesulfonate
(TIPS-triflate) in the presence of lutidine in DCM
at 0°C afforded di-protected compound 179 in 94% yield.
Selective deprotection of the TIPS group at position 32
using p-TSA in MeOH at rt gave mono-protected macrolide
180 in 88% yield. Reaction of the hydroxyl group at
position 32 with o-nitrobenzenesulfonyl chloride (181) in
the presence of DMAP and DIPEA in DCM provided 182 in
78% yield with 20% recovered starting material 180.
Displacement of the sulfate with chloride using LiCl in
DMF furnished the chlorinated compound, which was
treated with aqueous HF to remove the TIPS group to
provide pimecrolimus (21).
Veterinary Drugs and Treatments
A relatively new addition to the human topical armamentarium, pimecrolimus cream may be of benefit in veterinary patients in the
adjunctive treatment of atopic dermatitis, discoid lupus erythematosus, pemphigus erythematosus or foliaceous, pinnal vascular disease,
alopecia areata, vitiligo and for perianal fistulas (terminal phase or maintenance treatment after cyclosporine therapy). Unlike topical
corticosteroids, tacrolimus or pimecrolimus do not have atrophogenic or metabolic effects associated with long-term or large area
treatment.
Pimecrolimus acts similarly as cyclosporine and tacrolimus, namely inhibiting T-lymphocyte activation primarily by inhibiting the
phosphatase activity of calcineurin. It also inhibits the release of inflammatory cytokines and mediators from mast cells and basophils.
Pimecrolimus may not have identical mechanisms of action as tacrolimus, as it did not impair the primary immune response (as did
tacrolimus) in mice after a contact sensitizer was applied. Both drugs did impair the secondary response however. Any clinical significance
associated with this difference is not yet clear.
references
[1]. stuetz a, grassberger m, meingassner jg. pimecrolimus (elidel, sdz asm 981)--preclinical pharmacologic profile and skin selectivity. semin cutan med surg, 2001, 20(4): 233-241.[2]. zuberbier t, chong su, grunow k, et al. the ascomycin macrolactam pimecrolimus (elidel, sdz asm 981) is a potent inhibitor of mediator release from human dermal mast cells and peripheral blood basophils. j allergy clin immunol, 2001, 108(2): 275-280.[3]. kalthoff fs, chung j, stuetz a. pimecrolimus inhibits up-regulation of ox40 and synthesis of inflammatory cytokines upon secondary t cell activation by allogeneic dendritic cells. clin exp immunol, 2002, 130(1): 85-92.
Check Digit Verification of cas no
The CAS Registry Mumber 137071-32-0 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 1,3,7,0,7 and 1 respectively; the second part has 2 digits, 3 and 2 respectively.
Calculate Digit Verification of CAS Registry Number 137071-32:
(8*1)+(7*3)+(6*7)+(5*0)+(4*7)+(3*1)+(2*3)+(1*2)=110
110 % 10 = 0
So 137071-32-0 is a valid CAS Registry Number.
InChI:InChI=1/C43H68ClNO11/c1-10-30-18-24(2)17-25(3)19-36(53-8)39-37(54-9)21-27(5)43(51,56-39)40(48)41(49)45-16-12-11-13-32(45)42(50)55-38(28(6)33(46)23-34(30)47)26(4)20-29-14-15-31(44)35(22-29)52-7/h18,20,25,27-33,35-39,46,51H,10-17,19,21-23H2,1-9H3/b24-18+,26-20+/t25-,27+,28-,29-,30+,31-,32-,33-,35+,36-,37-,38+,39+,43+/m0/s1
137071-32-0Relevant articles and documents
PROCESS TO CONVERT CRUDE ASCOMYCIN INTO PURIFIED PIMECROLIMUS
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Paragraph 0069-0080, (2018/11/26)
The present disclosure is directed to an improved process to convert crude ascomycin to purified pimecrolimus. Crude ascomycin is chlorinated with triphenylphosphine and N-chlorosuccinimide (NCS) to yield crude pimecrolimus, which is then purified further by HPLC and subsequent crystallization. The processes of the present disclosure enable the removal of close homologs of pimecrolimus by high-pressure liquid chromatography without prior purification of the ascomycin starting material. This improvement may make the conversion of ascomycin to pimecrolimus industrially applicable and less expensive.
A CHEMO-ENZYMATIC APPROACH TO THE SYNTHESIS OF PIMECROLIMUS
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Page/Page column 19, (2010/12/18)
Processes for preparing pimecrolimus starting from ascomycin, exploiting the selectivity characteristics of the purified enzymatic systems particularly regarding the selective functionalization of the hydroxyl groups present in position 24 and 33 of ascomycin. Such method represents the first example of chemoenzymatic synthesis for preparing pimecrolimus.
Heteroatoms-Containing Tricyclic Compounds
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Page/Page column 3, (2008/06/13)
A process for the production of 33-Epi-33-chloro-FR 520 in one step from FR520 wherein protecting groups are avoided.