Discovery of 4-Morpholino-6-aryl-1H-pyrazolo[3,4-d]pyrimidines as Highly Potent and Selective ATP-Competitive Inhibitors of the Mammalian Target of Rapamycin (mTOR): Optimization of the 6-Aryl Substituent
Verheijen, JC; Richard, DJ; Curran, K; Kaplan, J; Lefever, M; Nowak, P; Malwitz, DJ; Brooijmans, N; Toral-Barza, L; Zhang, WG; Lucas, J; Hollander, I; Ayral-Kaloustian, S; Mansour, TS; Yu, K; Zask, A
| HERO ID | 406810 |
|---|---|
| In Press | No |
| Year | 2009 |
| Title | Discovery of 4-Morpholino-6-aryl-1H-pyrazolo[3,4-d]pyrimidines as Highly Potent and Selective ATP-Competitive Inhibitors of the Mammalian Target of Rapamycin (mTOR): Optimization of the 6-Aryl Substituent |
| Authors | Verheijen, JC; Richard, DJ; Curran, K; Kaplan, J; Lefever, M; Nowak, P; Malwitz, DJ; Brooijmans, N; Toral-Barza, L; Zhang, WG; Lucas, J; Hollander, I; Ayral-Kaloustian, S; Mansour, TS; Yu, K; Zask, A |
| Journal | Journal of Medicinal Chemistry |
| Volume | 52 |
| Issue | 24 |
| Page Numbers | 8010-8024 |
| Abstract | Design and synthesis of a series of 4-morpholino-6-aryl-1H-pyrazolo[3,4-d]pyrimidines as potent and selective inhibitors of the mammalian target of rapamycin (mTOR) are described. Optimization of the 6-aryl substituent led to the discovery of inhibitors carrying 6-ureidophenyl groups, the first reported active site inhibitors of mTOR with subnanomolar inhibitory concentrations. The data presented in this paper show that 6-arylureidophenyl substituents led to potent mixed inhibitors of mTOR and phosphatidylinositol 3-kinase α (PI3K-α), whereas 6-alkylureidophenyl appendages gave highly selective mTOR inhibitors. Combination of 6-alkylureidophenyl groups with 1-carbamoylpiperidine substitution resulted in compounds with subnanomolar IC50 against mTOR and greater than 1000-fold selectivity over PI3K-α. In addition, structure based drug design resulted in the preparation of several 6-arylureidophenyl-1H-pyrazolo[3,4-d]pyrimidines, substituted in the 4-position of the arylureido moiety with water solubilizing groups. These compounds combined potent mTOR inhibition (IC50 < 1 nM) with unprecedented activity in cellular proliferation assays (IC50 < 1 nM). |
| Doi | 10.1021/jm9013828 |
| Is Certified Translation | No |
| Dupe Override | No |
| Comments | Scopus URL: https://www.scopus.com/inward/record.uri?eid=2-s2.0-73249124369&doi=10.1021%2fjm9013828&partnerID=40&md5=05b0edd9a29d472d8bb37431317d4dee |
| Is Public | Yes |
| Language Text | English |
| Keyword | 1 [4 [1 (1 benzylpiperidin 4 yl) 4 morpholin 4 yl 1h pyrazolo[3,4 d]pyrimidin 6 yl]phenyl] 3 (1h imidazol 2 yl)urea; 1 [4 [1 (1 benzylpiperidin 4 yl) 4 morpholin 4 yl 1h pyrazolo[3,4 d]pyrimidin 6 yl]phenyl] 3 cyclopropylurea; 4 (4 morpholin 4 yl 1 phenyl 1h pyrazolo[3,4 d]pyrimidin 6 yl)aniline; 4 (6 chloro 4 morpholin 4 ylpyrazolo[3,4 d]pyrimidin 1 yl)piperidine 1 carboxylic acid methyl ester; 4 [1 (1 benzylpiperidin 4 yl) 4 morpholin 4 yl 1h pyrazolo[3,4 d]pyrimidin 6 yl]aniline; 4 [1 (1 benzylpiperidin 4 yl) 4 morpholin 4 yl 1h pyrazolo[3,4 d]pyrimidin 6 yl]phenyl]acetic acid; 5 (4 morpholino 1 phenyl 1h pyrazolo[3,4 d]pyrimidin 6 yl) pyridin 2 amine; isopropyl 4 (6 chloro 4 morpholin 4 yl 1h pyrazolo[3,4 d]pyrimidin 1 yl)piperidine 1 carboxylate; isopropyl 4 [6 (4 aminophenyl) 4 morpholin 4 yl 1h pyrazolo [3,4 d]pyrimidin 1 yl]piperidine 1 carboxylate; isopropyl 4 [6 [4 (3 methylureido)phenyl] 4 morpholino 1h pyrazolo[3,4 d]pyrimidin 1 yl]piperidine 1 carboxylate; mammalian target of rapamycin inhibitor; methyl 4 [4 morpholino 6 [4 [3 [4 [2 (pyrrolidin 1 yl)ethyl]phenyl]ureido]phenyl] 1h pyrazolo[3,4 d]pyrimidin 1 yl]piperidine 1 carboxylate; methyl 4 [6 (4 aminophenyl) 4 morpholin 4 yl 1h pyrazolo [3,4 d]pyrimidin 1 yl]piperidine 1 carboxylate; methyl 4 [6 [4 (3 methylureido)phenyl] 4 morpholino 1h pyrazolo[3,4 d]pyrimidin 1 yl]piperidine 1 carboxylate; methyl [4 (4 morpholin 4 yl 1 phenyl 1h pyrazolo[3,4 d]pyrimidin 6 yl)phenyl]carbamate; methyl [4 [1 (1 benzylpiperidin 4 yl) 4 morpholin 4 yl 1h pyrazolo[3,4 d]pyrimidin 6 yl]phenyl]carbamate; methyl [4 [4 morpholin 4 yl 1 [1 (pyridin 3 ylmethyl)piperidin 4 yl] 1h pyrazolo[3,4 d]pyrimidin 6 yl]phenyl]carbamate; n [4 (4 morpholin 4 yl 1 phenyl 1h pyrazolo[3,4 d]pyrimidin 6 yl)phenyl]acetamide; n [4 [1 (1 benzylpiperidin 4 yl) 4 morpholin-4-yl-1H-pyrazolo[3,4 d]pyrimidin 6 yl]phenyl] n' methylurea; n methyl 4 (4 morpholino 1 phenyl 1h pyrazolo[3,4 d]pyrimidin 6 yl)aniline; phosphatidylinositol 3 kinase; phosphatidylinositol 3 kinase alpha; tert butyl 4 (6 chloro 4 morpholin 4 yl 1h pyrazolo[3,4 d]pyrimidin 1 yl)piperidine 1 carboxylate; tert butyl 4 [6 (4 aminophenyl) 4 morpholin 4 yl 1h pyrazolo [3,4 d]pyrimidin 1 yl]piperidine 1 carboxylate; tert butyl 4 [6 [4 (3 methylureido)phenyl] 4 morpholino 1h pyrazolo[3,4 d]pyrimidin 1 yl]piperidine 1 carboxylate; unclassified drug; animal experiment; animal model; article; cell proliferation; controlled study; drug activity; drug design; drug structure; female; human; IC 50; mouse; nonhuman; structure activity relation; Suzuki reaction; Adenosine Triphosphate; Binding, Competitive; Cell Growth Processes; Cell Line, Tumor; Humans; Male; Models, Molecular; Morpholines; Prostatic Neoplasms; Protein Kinase Inhibitors; Protein Kinases; Pyrazoles; Pyrimidines; Structure-Activity Relationship |
| Is Qa | No |