Article

Cell Penetrant Inhibitors of the KDM4 and KDM5 Families of Histone Lysine Demethylases. 2. Pyrido[3,4-d]pyrimidin-4(3H)-one Derivatives

Susan M. Westaway^*^†, Alex G. S. Preston^*^†, Michael D. Barker^†, Fiona Brown^‡, Jack A. Brown^†, Matthew Campbell^†, Chun-wa Chung^‡, Gerard Drewes^§, Robert Eagle^‡, Neil Garton^†, Laurie Gordon^‡, Carl Haslam^‡, Thomas G. Hayhow^†, Philip G. Humphreys^†, Gerard Joberty^§, Roy Katso^‡, Laurens Kruidenier^†, Melanie Leveridge^‡, Michelle Pemberton^‡, Inma Rioja^†, Gail A. Seal^†, Tracy Shipley^†, Onkar Singh^‡, Colin J. Suckling^∥, Joanna Taylor^‡, Pamela Thomas^‡, David M. Wilson^†, Kevin Lee^†, and Rab K. Prinjha^†

^† Epinova Discovery Performance Unit, Medicines Research Centre, GlaxoSmithKline R&D, Stevenage SG1 2NY, U.K.

^‡ Platform Technology and Sciences, Medicines Research Centre, GlaxoSmithKline R&D, Stevenage SG1 2NY, U.K.

^§ Cellzome GmbH, a GSK Company, Meyerhofstrasse 1, 69117 Heidelberg, Germany

^∥ Department of Pure and Applied Chemistry, WestCHEM Research School, University of Strathclyde, Glasgow G1 1XL, U.K.

J. Med. Chem., 2016, 59 (4), pp 1370–1387

DOI: 10.1021/acs.jmedchem.5b01538

Publication Date (Web): January 15, 2016

*S.M.W.: e-mail, sue.m.westaway@gsk.com; telephone, +44 (0)1438763469., *A.G.S.P.: e-mail, alex.gs.preston@gsk.com; telephone, +44 (0)1438790152.

This article is part of the

Epigenetics

special issue.

Abstract

Following the discovery of cell penetrant pyridine-4-carboxylate inhibitors of the KDM4 (JMJD2) and KDM5 (JARID1) families of histone lysine demethylases (e.g., 1), further optimization led to the identification of non-carboxylate inhibitors derived from pyrido[3,4-d]pyrimidin-4(3H)-one. A number of exemplars such as compound 41 possess interesting activity profiles in KDM4C and KDM5C biochemical and target-specific, cellular mechanistic assays.

Supporting Information

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jmedchem.5b01538.

LCMS spectra and selectivity profiling data for 31, 32, 36, 39, and 41; KDM4C RFMS assay data for compounds 47–49; X-ray crystallography methods and data for compounds 3, 4, and 33 bound to KDM4D (PDF)
Molecular formula strings (CSV)

View: ACS ActiveView PDF | PDF | PDF w/ Links | Full Text HTML

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2017年3月18日土曜日

★ 血管の 欠陥 指数 ①

全ての病気は 血管 につながる。 個々の検査値に 一喜一憂 しないで血管＝欠陥状態 を把握する 簡便な指数

★ 肝機能を意識した改定版 ★

★ 欠 陥 指 数 ＝

＜脂質異常値： LDL/HDL＞ｘ ＜血圧＞ｘ ＜糖異常＞／＜年齢＞

他のリスクファクター がない場合（健全なワカモノ） は、

★欠陥指数＝＜ＬＤＬ／ＨＤＬ＞ ｘ ＜収縮期血圧／１００＞ ｘ ＜HbA1C／年齢（ｘ ０．１）＞

＝ ＜～２．５＞ｘ ＜～１．３＞ｘ ＜１．５＞ ＝ ＜ ～５

おおむね < ５ 以下 になりますが、

血圧とＨｂＡ１ｃ が高い人は 基準値 ＜L/H= ２．５＞

を 大きく超えるので、

＜ＬＤＬ／ＨＤＬ値＞と 欠陥指数 との間の差（引き算）

で 血管の欠陥度を 判定します。

【つまりは ＜ＬＤＬ／ＨＤＬ値＞ をベースにして それを ＜増幅するリスク因子＞ があるかを

数値化します。】

◆ 肝臓＝ダメージ度の 加算；

肝臓にダメージを与えるものは、たばこ、酒のほか

常用薬剤や サプリメント などが考えられます！

◆ たばこ愛煙家 の場合は リスクファクターにプラス １！

◆◆ 飲酒習慣者も リスクファクターにプラス １ ！！

肝臓指数： ＡＬＴ／ＡＳＴ または ＡＳＴ／ＡＬＴ

の値が １ を越えたら その 数値を

リスクファクター として 足す！！！

◆◆◆ 薬剤数の加算；

すでに ある種（数種）の薬剤を 服用している場合は、リスクファクターに ＜薬剤の種類数＞ を加える。

★★★ 感染指数＝ＣＲＰの活用：

さらに冬場や 蚊の繁殖 流行時には、

真の欠陥指数＝欠陥指数 ＋ 感染指数（ＣＲＰ)

＜通常ＣＲＰは ゼロに近い炎症蛋白 なので便利＞

2017年3月17日金曜日

CN As A Drug Discovery Scaffold

Ｓｅｅ Ｆｏｒ Ｅｘａｍｐｌｅｓ：

2017年3月15日水曜日

See For Examples;

2017年3月14日火曜日

Article

Cell Penetrant Inhibitors of the KDM4 and KDM5 Families of Histone Lysine Demethylases. 2. Pyrido[3,4-d]pyrimidin-4(3H)-one Derivatives

Abstract

PDF

Other ACS content by these authors:

See also:

Related Content:

Metrics

★　血管の　欠陥　指数　①　

全ての病気は　血管につながる。
個々の検査値に　一喜一憂しないで
血管＝欠陥状態　を把握する　簡便な指数

★　肝機能を意識した改定版　★　

★　欠　陥　指　数　＝

＜脂質異常値：　LDL/HDL＞ｘ　＜血圧＞ｘ　＜糖異常＞／＜年齢＞

他のリスクファクター　がない場合（健全なワカモノ）　は、

★欠陥指数＝＜ＬＤＬ／ＨＤＬ＞　ｘ＜収縮期血圧／１００＞
　　　　　　　　　　　　　　　　　　　ｘ＜HbA1C／年齢（ｘ　０．１）＞

　　　＝　＜～２．５＞ｘ＜～１．３＞ｘ＜１．５＞　＝＜　～５

おおむね　< ５　以下　になりますが、

血圧とＨｂＡ１ｃが高い人は基準値＜L/H=　２．５＞

を大きく超えるので、　

＜ＬＤＬ／ＨＤＬ値＞と欠陥指数との間の差（引き算）

で　血管の欠陥度を　判定します。

　【つまりは　＜ＬＤＬ／ＨＤＬ値＞　をベースにして
　それを　＜増幅するリスク因子＞　があるかを

◆　肝臓＝ダメージ度の　加算；

常用薬剤や　サプリメント　などが考えられます！

◆　　たばこ愛煙家の場合は　リスクファクターにプラス　１！

◆◆　飲酒習慣者も　リスクファクターにプラス　１　！！

肝臓指数：　　ＡＬＴ／ＡＳＴ　または　ＡＳＴ／ＡＬＴ

の値が　１　を越えたら　その　数値を

リスクファクター　として　足す！！！

◆◆◆　　薬剤数の加算；

すでに　ある種（数種）の薬剤を　服用している場合は、
リスクファクターに　＜薬剤の種類数＞　を加える。

★★★　　感染指数＝ＣＲＰの活用：

さらに冬場や　蚊の繁殖　流行時には、

真の欠陥指数＝欠陥指数＋感染指数（ＣＲＰ)

＜通常ＣＲＰは　ゼロに近い炎症蛋白　なので便利＞

Ｓｅｅ　Ｆｏｒ　Ｅｘａｍｐｌｅｓ：