405940-04-7Relevant academic research and scientific papers
Pyrazines and Pyridines and Derivatives Thereof as Therapeutic Compounds
-
Page/Page column 62, (2010/11/29)
The present invention pertains to certain pyrazines and pyridines, and derivatives thereof, which, inter alia, inhibit RAF (e.g., B RAF) activity, inhibit cell proliferation, treat cancer, etc., and more particularly to compounds of the formulae: (I) wherein: Q is independently —N═ or —CH═; one of RP2 and RP3 is independently a group of the formula -J1-L1-Z; wherein: if Q is —N═, then -J1-L1-Z is independently: —NH-Z; —O-Z; or S-Z; if Q is —CH═, then -J1-L1-Z is independently: —NH—(CH2)n-Z, wherein n is independently 0 or 1; —O-Z; or —S-Z; Z is independently: C6-14 carboaryl, C5-14 heteroaryl, C3-12carbocyclic, C3-12 heterocyclic; and is independently unsubstituted or substituted; the other of RP2 and RP3 is independently —H, —NHRN1, or —NHC(═O)RN2; wherein: RN1, if present, is independently —H or aliphatic saturated C1-4alkyl; RN2, if present, is independently —H or aliphatic saturated C1-4alkyl; one of RP5 and RP6 is independently a group of the formula —W—Y; wherein: W is independently: a covalent bond; —NRN4—, —O—, —S—, —C(═O)—, —CH2—; —NRN4—CH2—, —O—CH2—, —S—CH2—, —C(═O)—CH2—, —(CH2)2—; —CH2—NRN4—, —CH2—O—, —CH2—S—, or —CH2—C(═O)—; wherein RN4, if present, is independently —H or aliphatic saturated C1-4alkyl; Y is independently: C6-14carboaryl, C5-14heteroaryl, C3-12carbocyclic, C3-12heterocyclic; and is independently unsubstituted or substituted; the other of RP5 and RP6 is independently —H; and pharmaceutically acceptable salts, solvates, amides, esters, ethers, N-oxides, chemically protected forms, and prodrugs thereof. The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, e.g., both in vitro and in vivo, to inhibit RAF (e.g., B-RAF) activity, to inhibit receptor tyrosine kinase (RTK) activity, to inhibit cell proliferation, and in the treatment of diseases and conditions that are ameliorated by the inhibition of RAF, RTK, etc., proliferative conditions such as cancer (e.g., colorectal cancer, melanoma), etc.
Novel inhibitors of B-RAF based on a disubstituted pyrazine scaffold. Generation of a nanomolar lead
Niculescu-Duvaz, Ion,Roman, Esteban,Whittaker, Steven R.,Friedlos, Frank,Kirk, Ruth,Scanlon, Ian J.,Davies, Lawrence C.,Niculescu-Duvaz, Dan,Marais, Richard,Springer, Caroline J.
, p. 407 - 416 (2007/10/03)
B-RAF, a serine/threonine kinase, plays an important role in the development of certain classes of cancer, especially melanoma. As a result of high-throughput screening of a 23,000 compound library, 2-(3,4,5- trimethoxyphenylamino)-6-(3-acetamidophenyl)pyrazine, 1, was identified as a low micromolar (IC50 = 3.5 μM) B-RAF inhibitor. This compound was chosen as the starting point of a program aimed at producing potent inhibitors of B-RAF. We have synthesized a series of 40 novel compounds, which involved extensive modifications to the 2-(3,4,5-trimethoxyphenylamino) moiety (ring A) of 1. Their biological profiles against isolated B-RAF and mutated B-RAF in a cellular assay have been determined. These efforts led to the identification of two compounds exhibiting activities lower than 800 nM against B-RAF.
Synthesis and discovery of pyrazine-pyridine biheteroaryl as a novel series of potent vascular endothelial growth factor receptor-2 inhibitors
Kuo, Gee-Hong,Wang, Aihua,Emanuel, Stuart,DeAngelis, Alan,Zhang, Rui,Connolly, Peter J.,Murray, William V.,Gruninger, Robert H.,Sechler, Jan,Fuentes-Pesquera, Angel,Johnson, Dana,Middleton, Steven A.,Jolliffe, Linda,Chen, Xin
, p. 1886 - 1900 (2007/10/03)
Pathological angiogenesis is associated with disease states such as cancer, diabetic retinopathy, rheumatoid arthritis, endometriosis, and psoriasis. There is much evidence that direct inhibition of the kinase activity of vascular endothelial growth facto
