Temozolomide analogs with improved brain/plasma ratios - Exploring the possibility of enhancing the therapeutic index of temozolomide.
Temozolomide is a chemotherapeutic agent that is used in the treatment of glioblastoma and other malignant gliomas. It acts through DNA alkylation, but treatment is limited by its systemic toxicity and neutralization of DNA alkylation by upregulation of the O6-methylguanine-DNA methyltransferase gene. Both of these limiting factors can be addressed by achieving higher concentrations of TMZ in the brain. Our research has led to the discovery of new analogs of temozolomide with improved brain:plasma ratios when dosed in vivo in rats. These compounds are imidazotetrazine analogs, expected to act through the same mechanism as temozolomide. With reduced systemic exposure, these new agents have the potential to improve efficacy and therapeutic index in the treatment of glioblastoma.
Medivation, 525 Market Street, 36th Floor, San Francisco, CA 94105, USA.
Roopa
R
Rai
Curadev Pvt. Ltd, B-87, Sector 83, Noida, Uttar Pradesh 201305, India.
Monali
M
Banerjee
Concert Pharmaceuticals, 99 Hayden Ave, Suite 500, Lexington, MA 02421, USA.
Darren H
DH
Wong
Medivation, 525 Market Street, 36th Floor, San Francisco, CA 94105, USA.
Emma
E
McCullagh
Integral BioScience Pvt. Ltd, C-64, Hosiery Complex Phase II Extension, Noida, Uttar Pradesh 201306, India.
Ashu
A
Gupta
Integral BioScience Pvt. Ltd, C-64, Hosiery Complex Phase II Extension, Noida, Uttar Pradesh 201306, India.
Shailendra
S
Tripathi
Fundación Ciencia y Vida, Avenida Zañartu 1482, Ñuñoa, Santiago 7780272, Chile.
Eduardo
E
Riquelme
Integral BioScience Pvt. Ltd, C-64, Hosiery Complex Phase II Extension, Noida, Uttar Pradesh 201306, India.
Ramnivas
R
Jangir
Integral BioScience Pvt. Ltd, C-64, Hosiery Complex Phase II Extension, Noida, Uttar Pradesh 201306, India.
Shyamraj
S
Yadav
Integral BioScience Pvt. Ltd, C-64, Hosiery Complex Phase II Extension, Noida, Uttar Pradesh 201306, India.
Mohd
M
Raja
Integral BioScience Pvt. Ltd, C-64, Hosiery Complex Phase II Extension, Noida, Uttar Pradesh 201306, India.
Pankaj
P
Melkani
Integral BioScience Pvt. Ltd, C-64, Hosiery Complex Phase II Extension, Noida, Uttar Pradesh 201306, India.
Vikas
V
Dixit
Integral BioScience Pvt. Ltd, C-64, Hosiery Complex Phase II Extension, Noida, Uttar Pradesh 201306, India.
Umesh
U
Patil
Curadev Pvt. Ltd, B-87, Sector 83, Noida, Uttar Pradesh 201305, India.
Ritesh
R
Shrivastava
Curadev Pvt. Ltd, B-87, Sector 83, Noida, Uttar Pradesh 201305, India.
Sandip
S
Middya
Fundación Ciencia y Vida, Avenida Zañartu 1482, Ñuñoa, Santiago 7780272, Chile.
Felipe
F
Olivares
Fundación Ciencia y Vida, Avenida Zañartu 1482, Ñuñoa, Santiago 7780272, Chile.
Javier
J
Guerrero
Curadev Pvt. Ltd, B-87, Sector 83, Noida, Uttar Pradesh 201305, India.
Arjun
A
Surya
Medivation, 525 Market Street, 36th Floor, San Francisco, CA 94105, USA.
Son M
SM
Pham
Medivation, 525 Market Street, 36th Floor, San Francisco, CA 94105, USA.
Sebastián
S
Bernales
Medivation, 525 Market Street, 36th Floor, San Francisco, CA 94105, USA.
Andrew A
AA
Protter
Medivation, 525 Market Street, 36th Floor, San Francisco, CA 94105, USA.
David T
DT
Hung
Medivation, 525 Market Street, 36th Floor, San Francisco, CA 94105, USA.
Sarvajit
S
Chakravarty
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D019540:Area Under Curve; D001921:Brain / Q000378:metabolism*; D045744:Cell Line, Tumor; D002853:Chromatography, Liquid; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D051381:Rats; D053719:Tandem Mass Spectrometry; D000077204:Temozolomide
D018906:Antineoplastic Agents, Alkylating; D003606:Dacarbazine; D000077204:Temozolomide
Chemotheraphy; Glioblastoma; O(6)-Methyl-2′-deoxyguanosine (O(6)-MedG); Temozolomide