- Improvement of Aqueous Solubility of Lapatinib-Derived Analogues: Identification of a Quinolinimine Lead for Human African Trypanosomiasis Drug Development
-
Lapatinib, an approved epidermal growth factor receptor inhibitor, was explored as a starting point for the synthesis of new hits against Trypanosoma brucei, the causative agent of human African trypanosomiasis (HAT). Previous work culminated in 1 (NEU-1953), which was part of a series typically associated with poor aqueous solubility. In this report, we present various medicinal chemistry strategies that were used to increase the aqueous solubility and improve the physicochemical profile without sacrificing antitrypanosomal potency. To rank trypanocidal hits, a new assay (summarized in a cytocidal effective concentration (CEC50)) was established, as part of the lead selection process. Increasing the sp3 carbon content of 1 resulted in 10e (0.19 μM EC50 against T. brucei and 990 μM aqueous solubility). Further chemical exploration of 10e yielded 22a, a trypanocidal quinolinimine (EC50: 0.013 μM; aqueous solubility: 880 μM; and CEC50: 0.18 μM). Compound 22a reduced parasitemia 109 fold in trypanosome-infected mice; it is an advanced lead for HAT drug development.
- Bachovchin, Kelly A.,Sharma, Amrita,Bag, Seema,Klug, Dana M.,Schneider, Katherine M.,Singh, Baljinder,Jalani, Hitesh B.,Buskes, Melissa J.,Mehta, Naimee,Tanghe, Scott,Momper, Jeremiah D.,Sciotti, Richard J.,Rodriguez, Ana,Mensa-Wilmot, Kojo,Pollastri, Michael P.,Ferrins, Lori
-
p. 665 - 687
(2019/01/21)
-
- Xanthate-mediated intermolecular alkylation of pyrazines
-
An expedient approach for the intermolecular C-H functionalization of pyrazines and other heteroarenes by the radical chemistry of xanthates is reported. Incorporation of a multitude of functional alkyl groups onto these heteroarenes proceeds in good yiel
- Huang, Qi,Qin, Ling,Zard, Samir Z.
-
supporting information
p. 5804 - 5817
(2018/09/21)
-
- Efficient and versatile catalytic systems for the n-methylation of primary amines with methanol catalyzed by n-heterocyclic carbene complexes of iridium
-
Efficient and versatile catalytic systems were developed for the N-methylation of both aliphatic and aromatic primary amines using methanol as the methylating agent. Iridium complexes bearing an Nheterocyclic carbene (NHC) ligand exhibited high catalytic performance for this type of transformation. For aliphatic amines, selective N,N-dimethylation was achieved at low temperatures (50-90 °C). For aromatic amines, selective N-monomethylation and selective N,N-dimethylation were accomplished by simply changing the reaction conditions (presence or absence of a base with an appropriate catalyst). These findings can be used to develop methods for synthesizing useful amine compounds having N-methyl or N,N-dimethyl moieties.
- Toyooka, Genki,Tuji, Akiko,Fujita, Ken-Ichi
-
p. 4617 - 4626
(2019/02/01)
-
- N-Methylation of Amines with Methanol Catalyzed by a Cp?Ir Complex Bearing a Functional 2,2′-Bibenzimidazole Ligand
-
A new type of Cp?Ir complex bearing a functional 2,2′-bibenzimidazole ligand was designed, synthesized, and found to be a highly effective and general catalyst for the N-methylation of a variety of amines with methanol in the presence of a weak base (0.3 equiv of Cs2CO3).
- Liang, Ran,Li, Shun,Wang, Rongzhou,Lu, Lei,Li, Feng
-
supporting information
p. 5790 - 5793
(2017/11/10)
-
- General and efficient method for direct N-monomethylation of aromatic primary amines with methanol
-
The direct N-monomethylation of aromatic primary amines, including arylamines, arylsulfonamides and amino-azoles, using methanol as a methylating agent has been accomplished in the presence of a [CpIrCl2]2/NaOH system. From both synthetic and environmental points of view, the reaction is highly attractive because of low catalyst loading, broad substrate scope and excellent selectivities.
- Li, Feng,Xie, Jianjiang,Shan, Haixia,Sun, Chunlou,Chen, Lin
-
p. 8645 - 8652
(2015/03/05)
-
- 2,3-Diaminopyrazines as rho kinase inhibitors
-
Inhibition of rho kinase (ROCK) has been recognized as an important target for a number of diseases, including glaucoma. Herein we report SAR development around two hits from a kinase library that led to the discovery of the ROCK inhibitor compound 38. In vitro and in vivo analysis of this compound, including its effects in a monkey model of glaucoma will be discussed.
- Henderson, Alan J.,Hadden, Mark,Guo, Cheng,Douglas, Neema,Decornez, Helene,Hellberg, Mark R.,Rusinko, Andrew,McLaughlin, Marsha,Sharif, Naj,Drace, Colene,Patil, Raj
-
scheme or table
p. 1137 - 1140
(2010/06/15)
-
- Aminopyrazine analogs for treating glaucoma and other rho kinase-mediated diseases and conditions
-
Methods for using aminopyrazine analogs to treat rho kinase-mediated diseases or rho kinase-mediated conditions, including controlling intraocular pressure and treating glaucoma, are disclosed. Ophthalmic pharmaceutical compositions useful in the treatment of eye diseases such as glaucoma, and additionally useful for controlling intraocular pressure, the compositions comprising an effective amount of aminopyrazine analogs, are also disclosed.
- -
-
Page/Page column 5; 16
(2008/06/13)
-