Water-soluble prodrugs of an Aurora kinase inhibitor.
Compound 1 (SNS-314) is a potent and selective Aurora kinase inhibitor that is currently in clinical trials in patients with advanced solid tumors. This communication describes the synthesis of prodrug derivatives of 1 with improved aqueous solubility profiles. In particular, phosphonooxymethyl-derived prodrug 2g has significantly enhanced solubility and is converted to the biologically active parent (1) following iv as well as po administration to rodents.
Oslob
Johan D
JD
Sunesis Pharmaceuticals, Inc., 395 Oyster Point Boulevard, South San Francisco, CA 94080, USA.
Heumann
Stacey A
SA
Yu
Chul H
CH
Allen
Darin A
DA
Baskaran
Subramanian
S
Bui
Minna
M
Delarosa
Erlie
E
Fung
Amy D
AD
Hashash
Ahmad
A
Hau
Jonathan
J
Ivy
Sheryl
S
Jacobs
Jeffrey W
JW
Lew
Willard
W
Maung
Jack
J
McDowell
Robert S
RS
Ritchie
Sean
S
Romanowski
Michael J
MJ
Silverman
Jeffrey A
JA
Yang
Wenjin
W
Zhong
Min
M
Fuchs-Knotts
Tarra
T
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D064127:Aurora Kinases; D008297:Male; D051379:Mice; D010671:Phenylurea Compounds / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D011355:Prodrugs / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D013844:Thiazoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D014867:Water / Q000737:chemistry*
D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D011355:Prodrugs; C532454:SNS 314; D013844:Thiazoles; D014867:Water; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases