- WDR5 INHIBITORS AND MODULATORS
-
Quinazolin-4(3H)-one, 2,3 -dihydroquinazolin-4(1H)-one, 3,4-dihydrobenzo[f][1,4]oxazepin- 5(2H)-one, and 3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione compounds and derivatives inhibit WDR5 and associated protein-protein interactions, and the compounds and their pharmaceutical compositions are useful for treating disorders and conditions in a subject, such as cancer cell proliferation.
- -
-
Paragraph 00168
(2020/12/29)
-
- Ligand efficiency based approach for efficient virtual screening of compound libraries
-
Here we report for the first time the use of fit quality (FQ), a ligand efficiency (LE) based measure for virtual screening (VS) of compound libraries. The LE based VS protocol was used to screen an in-house database of 125,000 compounds to identify aurora kinase A inhibitors. First, 20 known aurora kinase inhibitors were docked to aurora kinase A crystal structure (PDB ID: 2W1C); and the conformations of docked ligand were used to create a pharmacophore (PH) model. The PH model was used to screen the database compounds, and rank (PH rank) them based on the predicted IC50 values. Next, LE-Scale, a weight-dependant LE function, was derived from 294 known aurora kinase inhibitors. Using the fit quality (FQ = LE/LE-Scale) score derived from the LE-Scale function, the database compounds were reranked (PH-FQ rank) and the top 151 (0.12% of database) compounds were assessed for aurora kinase A inhibition biochemically. This VS protocol led to the identification of 7 novel hits, with compound 5 showing aurora kinase A IC50 = 1.29 μM. Furthermore, testing of 5 against a panel of 31 kinase reveals that it is selective toward aurora kinase A & B, with 50% inhibition for other kinases at 10 μM concentrations and is a suitable candidate for further development. Incorporation of FQ score in the VS protocol not only helped identify a novel aurora kinase inhibitor, 5, but also increased the hit rate of the VS protocol by improving the enrichment factor (EF) for FQ based screening (EF = 828), compared to PH based screening (EF = 237) alone. The LE based VS protocol disclosed here could be applied to other targets for hit identification in an efficient manner.
- Ke, Yi-Yu,Coumar, Mohane Selvaraj,Shiao, Hui-Yi,Wang, Wen-Chieh,Chen, Chieh-Wen,Song, Jen-Shin,Chen, Chun-Hwa,Lin, Wen-Hsing,Wu, Szu-Huei,Hsu, John T.A.,Chang, Chung-Ming,Hsieh, Hsing-Pang
-
p. 226 - 235
(2014/07/08)
-
- Derivatives of 1,4-bis(3-hydroxycarbonyl-4-hydroxyl)styrylbenzene as PTP1B inhibitors with hypoglycemic activity
-
Disalicylic acid derivatives with stilbene and bis-styrylbenzene skeleton were synthesized as PTP1B inhibitors. The most potent in this series exhibited a submicromolar IC50 value. One of the compounds 7b was tested in an animal model for its efficacy as an anti-diabetic or an anti-obesity agent. In feeding compound 7b to diet-induced obese mice, no significant differences in weight gain and food consumption were observed between the drug-treated and the obese control mice. However, 7b significantly lowered the fasting glucose level and improved the glucose tolerance in the obesity-induced diabetic mice.
- Shrestha, Suja,Bhattarai, Bharat Raj,Kafle, Bhooshan,Lee, Keun-Hyeung,Cho, Hyeongjin
-
p. 8643 - 8652
(2008/12/23)
-
- 4-Phenyl-5-Oxo-1,4,5,6,7,8,- Hexahydroquinoline Derivatives as Medicaments for the Treatment of Infertility
-
The invention relates to a 4-phenyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline derivative according to Formula (I), wherein the substituents are defined as in the description, or a pharmaceutically salt thereof. The compounds of this invention are potent FSH receptor activators and may be used for treating fertility disorders in e.g. controlled ovarian hyperstimulation and IVF procedures.
- -
-
Page/Page column 27
(2009/01/20)
-
- Mono- and disalicylic acid derivatives: PTP1B inhibitors as potential anti-obesity drugs
-
A series of compounds containing one or two salicylic acid moieties were synthesized, and their efficacy to inhibit the phosphohydrolase activity of PTP1B examined. Some of the methylenedisalicylic acid derivatives were potent inhibitors of PTP1B. Of those derivatives, 3c exhibited about a 14-fold selectivity against TC-PTP, and this compound was tested in a mouse model for its efficacy to prevent diet-induced obesity. It effectively suppressed the increases in body weight and adipose mass, without any noticeable toxic effect. The compound also prevented increases in the plasma triglyceride, cholesterol, and nonesterified fatty acid concentrations; thus, expanding its therapeutic potential to other related metabolic diseases, such as hyperlipidemia and hypercholesterolemia.
- Shrestha, Suja,Bhattarai, Bharat Raj,Lee, Keun-Hyeung,Cho, Hyeongjin
-
p. 6535 - 6548
(2008/04/12)
-
- 4-PHENYL-5-OXO-l,4,5,6,7,8-HEXAHYDROQUINOLINE DERIVATIVES AS MEDICAMENTS FOR THE TREATMENT OF INFERTILITY
-
The invention relates to a 4-phenyl-5-oxo-l,4,5,6,7,8-hexahydroquinoline derivative according to Formula (I), wherein the substituents are defined as in the description, or a pharmaceutically salt thereof. The compounds of this invention are potent FSH receptor activators and may be used for treating fertility disorders in e.g. controlled ovarian hyperstimulation and IVF procedures.
- -
-
-