1095173-27-5 Usage
Uses
Glasdegib acts as a potent, orally biovailablesmoothened (Smo) inhibitor used in the treatment of cancer.
Biological Activity
pf-04449913 is an orally bioavailable inhibitor of smoothened with ic50 value of 5nm [1].in the hedgehog (hh) signaling pathway, the combination of hh ligands and their receptor patched leads to the activation of smoothened and subsequently activation of three transcription factors gli1, gli2 and gli3. it then leads to the proliferation of cells. as an antagonist of smoothened, pf-04449913 is developed for treatment of cancer [1].pf-04449913 is found not to inhibit cytochrome p450 and is negative in ames and micronucleus assays suggesting it as a safe drug. in the preclinical studies, pf-04449913 shows a half-life of 30 h and an oral bioavailability of 55% in humans. it also has low plasma clearance of 1.03 ml/min/kg and moderate volume of distribution (2.7 l/kg) [1].
Biochem/physiol Actions
PF-04449913 maleate salt is also known as 1-((2R,4R)-2-(1H-benzo[d]imidazol-2-yl)-1-methylpiperidin-4-yl)-3-(4-cyanophenyl)urea. It increases the differentiation of blood cells from hematopoietic precursors of the lymph gland medullary zone. This human Smo inhibitor protein is now under clinical trials to treat myeloid malignancies.
PF-04449913 (Glasdegib) is an orally bioavailable Hedgehog pathway inhibitor. PF-04449913 acts by binidng Smoothened (Smo) and blocking signal transduction. PF-04449913 has an IC50 of 5 nM in the Gli-Luciferase assay. In a Phase I clinical trial in patients with advanced solid tumors, PF-04449913 caused disease stabilization in 34% of patients.
references
[1] munchhof mj, li q, shavnya a, borzillo gv, boyden tl, jones cs, lagreca sd, martinez-alsina l, patel n, pelletier k, reiter la, robbins md, tkalcevic gt. discovery of pf-04449913, a potent and orally bioavailable inhibitor of smoothened. acs med chem lett. 2011 dec 21;3(2):106-11.
Check Digit Verification of cas no
The CAS Registry Mumber 1095173-27-5 includes 10 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 7 digits, 1,0,9,5,1,7 and 3 respectively; the second part has 2 digits, 2 and 7 respectively.
Calculate Digit Verification of CAS Registry Number 1095173-27:
(9*1)+(8*0)+(7*9)+(6*5)+(5*1)+(4*7)+(3*3)+(2*2)+(1*7)=155
155 % 10 = 5
So 1095173-27-5 is a valid CAS Registry Number.
1095173-27-5Relevant articles and documents
PROCESSES FOR THE PREPARATION OF GLASDEGIB AND SALT THEREOF AND SOLID STATE FORMS OF GLASDEGIB MALEATE AND PROCESS FOR PREPARATION THEREOF
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Paragraph 00187-00189; 00192; 00197-00199; 00206; 00200, (2021/08/06)
The present disclosure relates to safe and efficient processes for the synthesis of Glasdegib or salts thereof, preferably Glasdegib Maleate. The present disclosure also encompasses solid state forms of Glasdegib maleate, in embodiments crystalline polymorphs of Glasdegib maleate, processes for preparation thereof, and pharmaceutical compositions thereof.
Discovery of PF-04449913, a potent and orally bioavailable inhibitor of smoothened
Munchhof, Michael J.,Li, Qifang,Shavnya, Andrei,Borzillo, Gary V.,Boyden, Tracey L.,Jones, Christopher S.,Lagreca, Susan D.,Martinez-Alsina, Luis,Patel, Nandini,Pelletier, Kathleen,Reiter, Larry A.,Robbins, Michael D.,Tkalcevic, George T.
, p. 106 - 111 (2012/04/04)
Inhibitors of the Hedgehog signaling pathway have generated a great deal of interest in the oncology area due to the mounting evidence of their potential to provide promising therapeutic options for patients. Herein, we describe the discovery strategy to overcome the issues inherent in lead structure 1 that resulted in the identification of Smoothened inhibitor 1-((2R,4R)-2-(1H-benzo[d] imidazol-2-yl)-1-methylpiperidin-4-yl)-3-(4-cyanophenyl)urea (PF-04449913, 26), which has been advanced to human clinical studies.
