Cyano (=COOH) Pyridine Scaffolds 2018

"2-Amino-4-Cyano" Pyridines 2018 

 

 

https://pubs.acs.org/doi/10.1021/acsmedchemlett.8b00108

Brain Penetrant PDE=2A Inhibitor Drug Candidate 2018

PDE Inhibitors Scaffolds 2018

Cyano-Pyridine Scaffolds Selected in 2018

CyanoPyridine Scaffolds Selected :

 

Discovery of AG-120 (Ivosidenib): A First-in-Class Mutant IDH1 Inhibitor for the Treatment of IDH1 Mutant Cancers

 

 

Janeta Popovici-Muller^†∇, René M. Lemieux^†⊥, Erin Artin^†⊥, Jeffrey O. Saunders^†#, Francesco G. Salituro^†▲ , Jeremy Travins^†□, Giovanni Cianchetta^†, Zhenwei Cai^‡, Ding Zhou^‡⊗, Dawei Cui^‡, Ping Chen^‡, Kimberly Straley^†∞, Erica Tobin^†⊥, Fang Wang^†, Muriel D. David^∥, Virginie Penard-Lacronique^∥, Cyril Quivoron^∥, Véronique Saada^∥, Stéphane de Botton^∥, Stefan Gross^†, Lenny Dang^†, Hua Yang^†, Luke Utley^†@, Yue Chen^†, Hyeryun Kim^†, Shengfang Jin^†, Zhiwei Gu^§, Gui Yao^§, Zhiyong Luo^§, Xiaobing Lv^§, Cheng Fang^§, Liping Yan^§, Andrew Olaharski^†+, Lee Silverman^†, Scott Biller^†, Shin-San M. Su^†∇, and Katharine Yen^*†

^† Agios Pharmaceuticals Inc., Cambridge, Massachusetts 02139, United States

^‡ PharmaResources, Shanghai 201201, China

^§ ChemPartner, Shanghai 201203, China

^∥ INSERM U1170 and Gustave Roussy, Villejuif 94800, France

ACS Med. Chem. Lett., Article ASAP

DOI: 10.1021/acsmedchemlett.7b00421

Publication Date (Web): January 19, 2018

Copyright © 2018 American Chemical Society

*E-mail: katharine.yen@agios.com.

ACS AuthorChoice - This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes.

Cite this:ACS Med. Chem. Lett.  XXXX, XXX, XXX-XXX

Abstract

 

 

 

Somatic point mutations at a key arginine residue (R132) within the active site of the metabolic enzyme isocitrate dehydrogenase 1 (IDH1) confer a novel gain of function in cancer cells, resulting in the production of d-2-hydroxyglutarate (2-HG), an oncometabolite. Elevated 2-HG levels are implicated in epigenetic alterations and impaired cellular differentiation. IDH1 mutations have been described in an array of hematologic malignancies and solid tumors. Here, we report the discovery of AG-120 (ivosidenib), an inhibitor of the IDH1 mutant enzyme that exhibits profound 2-HG lowering in tumor models and the ability to effect differentiation of primary patient AML samples ex vivo. Preliminary data from phase 1 clinical trials enrolling patients with cancers harboring an IDH1 mutation indicate that AG-120 has an acceptable safety profile and clinical activity.

Keywords:

2-hydroxyglutarate; AG-120; differentiation therapy; isocitrate dehydrogenase; ivosidenib; mutant IDH1

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsmedchemlett.7b00421.

• Synthesis and profiling of AG-120, experimental procedures, synthetic details and characterization of compounds, and abbreviations (PDF)

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• PDF

  • ml7b00421_si_001.pdf (1 MB)

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Discovery of AG-120 (Ivosidenib):

Protein Kinase Inhibitor for Lymphatic Filariasis

Dual GSK-3β/AChE Inhibitors

 

NO2 or CN Attached Drug Substances 2018 =1

アザチオプリン

 

Azathiopurine

https://ja.wikipedia.org/wiki/%E3%82%A2%E3%82%B6%E3%83%81%E3%82%AA%E3%83%97%E3%83%AA%E3%83%B3

Leaving From The Private Library !! 2018

Pan-Assay Interference Compounds

https://pubs.acs.org/doi/abs/10.1021/acschembio.7b00903?src=recsys

The Rising and Falling Scaffolds 2018

It Also ＨＡＰＰＥＮＳ

 

In Modern Medicinal Chemistry Research:

 

 

https://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.7b00954?src=recsys

 

ジェネリック薬が 教えてくれるもの。

 

 

　

ジェネリック薬がおしえてくれることは多い。

 

なぜ売れるのか、なぜ安全なのか、どこが売りなのか。

考えるべきことはいくらも沸いてくるが、

 

真実は見えないことが多い。

多くの事実は結果であり、それは真実を包んだ銅像

 

の如き静止画である。

解説者は何とでも美辞麗句を並べるが、それは体裁の良い

理解しやすい方便（便宜）である。

 

事実から便宜を剥ぎ取り、見え難かったものに迫ることが

創薬のサイエンスとなり、未来の予見となる。

創薬のサイエンスに根ざさない　ランダムな合成と都合の良い評価

 

は 創薬のゴールに導く道標にはならない。

 

古い医薬品は　時のふるいにかけられた宝物

＝　創薬の原点であり、学ぶべき 手本である。

即ち　今あるジェネリック薬を 今ある最新の知識で解析し、

 

今求められるかたちに作り変える=ジェネリック装薬の途

 

について以下に紹介する。

 

 

　ジェネリック薬からの　ドラッグデザイン　試論　（！）　

 

すぐれた創薬の参考書は　枚挙にいとまがない。

多くの化合物をランダムに合成しその中から候補となるシーズを拾い上げる。

あるいは　自社の貴重な蓄積＝ライブラリー　から種を見つける。

そして　それを磨き上げ、最適化した候補＝リード　に持ち上げる。

ひたすら　サクセスストリーの道、巨人の星への途　であるが、それらを並べあげても

もはや　　《ドラッグデザイン》　　の古臭い結末ノ　ような気がするだけである。

 

手間隙のかかる　一見正統的な積み上げは重　要であるが、
なかなか骨がおれる。

おまけに、このような人海作戦は大グループのみで可能である。
そして今や大グループをもってしても新薬候補はなかなか　みつからない。

見つかったとしても　似たり寄ったりな化合物に落ち着くのが　関の山である。

なので、もっと簡便に、少人数で新薬の山に登れないのかと考えるのは

誰も同じ切望となる。一番手短なシーズあるいは　

お手本を頼りに　少人数でできる　インスタント創薬、あるいは

装薬の道はないものだろうかと考えて　一つのヒントとして浮かんできたのが

ジェネリック創薬への道　という愚考である。

 

 

以下　　リャク；

 

 

 

 

 

 

 

 

 

 

 

 

 

ＣＥＲＡＴＡＭＩＮＥ　Ａｓ　ＳＨ－ＲＡＤＩＣＬ　ＡＣＣＥＰＴＯＲ

Ceratamine From Trihaloimidazole via Beckmann Rearrangement:

 

 

 

Radical Drug Analysis 2014

スイニー（ジメチル基，メチル基の効果に注目！）

メチル基は　ラジカル安定化効果：

 

 

 

 

糖化反応阻害剤＝糖トラップ化アミン＝メトフォルミン

 

Ｓｅｅ　Ｆｏｒ　Ｇｏｏｄ　Ｅｘａｍｐｌｅｓ；

 

 

http://ebn.arkray.co.jp/disciplines/glycation/ages-08/

Pleiotropiv Effects of Pitavastatin 2011

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3376429/


and More;

Pitavastatin Pleiotropic Study

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4387666/

Conclusions

Pitavastatin not only improved atherosis measured by IMT and the sclerosis measured by cIBS values, but also attenuated inflammation of plaques at the same site as measured by max SUV. The present study indicated that pitavastatin had a stronger effect on regression and stabilization of plaques in the thoracic aorta compared with a mild hydrophilic statin.

Go to:

Acknowledgements

This study was funded by a grant from Japan vascular disease research foundation, Kyoto, Japan.

Cilostazol & ROCK 2016

See As Recent Opinions;

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5098914/

Simple Radical Metabolic Pathways for Anti-TB Drug & Others

 

Ｒａｄｉｃａｌ　Ｍｅｔａｂｏｌｉｃ　Ｐａｔｈｗａｙｓ

Ｆｏｒ　Ｉｓｏｎｉａｚｉｄ, Ｄｅｌａｍａｎｉｄ and Ｅｐａｌｒｅｓｔａｔ．

This Paper deals with the new radical metabolic patway
for two ant-TB drugs (Isoniazid and Delamanid) and one
ARI (aldose reductase inhibitor).

http://www.pnas.org/content/100/24/13881.full

Ｐｉｔａｖａｓｔａｔｉｎ　Ｗｏｒｋｓ　Ａｓ　ＲｈｏＡ

 

Ｉｎｖｅｒｓｅ　Ａｇｏｎｉｓｔ　Ｂｕｔ　Ｎｏｔ　ＧＰＣＲ１２０　Ｌｉｇａｎｄ．

欠陥指数 海底版 ２０１７

<欠陥指数>  改定版　＝ 　海底　深版　 ２０１８　

 

★　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＞

すなわち

 

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

 

 　＋　＜他のリスクファクター＞　！！

 

 

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＞

 

 

Isoniazid Metabolism 2016

See For Examples;

http://www.sciencedirect.com/science?_ob=ArticleListURL&_method=list&_ArticleListID=-1163636921&_sort=r&_st=13&view=c&md5=0562fa0a0db490ebe78128dda29bb4c0&searchtype=a

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5045547/

Bicyclic KDM Modulators 2016

Article

Previous Article

Next Article

Table of Contents

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

Copyright © 2016 American Chemical Society

*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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  • jm5b01538_si_001.pdf (1.15 MB)

• • jm5b01538_si_002.csv (2.71 kB)

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• 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
• Rab K. Prinjha

See also:

• Cell Penetrant Inhibitors of the KDM4 and KDM5 Families of Histone Lysine Demethylases. 1. 3-Amino-4-pyridine Carboxylate Derivatives
  Journal of Medicinal Chemistry

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• Cell Penetrant Inhibitors of the KDM4 and KDM5 Families of Histone Lysine Demethylases. 1. 3-Amino-4-pyridine Carboxylate Derivatives
  Journal of Medicinal Chemistry
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Article Views: 1,857 Times

Received 1 October 2015

Published online 15 January 2016

Published in print 25 February 2016

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Accession Codes

• PDB: 5FP9
• PDB: 5FPA
• PDB: 5FPB