Discovery and optimization of novel pyridines as highly potent and selective glycogen synthase kinase 3 inhibitors.,Bioorganic & Medicinal Chemistry Letters

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Discovery and optimization of novel pyridines as highly potent and selective glycogen synthase kinase 3 inhibitors.
Bioorganic & Medicinal Chemistry Letters ( IF 2.5 ) Pub Date : 2019-12-23 , DOI: 10.1016/j.bmcl.2019.126930
Savithri Ramurthy ₁ , Keith B Pfister ₂ , Rustum S Boyce ₃ , Sean P Brown ₄ , Abran Q Costales ₅ , Manoj C Desai ₆ , Eric Fang ₇ , Barry H Levine ₈ , Simon C Ng ₉ , John M Nuss ₁₀ , David B Ring ₁₁ , Cynthia M Shafer ₁₂ , Wei Shu ₂ , Sharadha Subramanian ₁₃ , Allan S Wagman ₁₄ , Haixia Wang ₁₅ , Dirksen E Bussiere ₂

Affiliation

HiberCell, Inc., 619 West 54th Street, New York, NY 10019, USA.
Global Discovery Chemistry, Novartis Institutes for BioMedical Research, 5300 Chiron Way, Emeryville, CA 94608, USA.
Vermont Biosynthetics LLC, 365 Glinnis Road, Northfield, VT 05663, USA.
Proneurotech, 161 Oyster Point Blvd., Suite 200, South San Francisco, CA 94080, USA.
Chevron Oronite Company LLC, 100 Chevron Way, Richmond, CA 94801, USA.
Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94404, USA.
Protein Sciences, Novartis Institutes for BioMedical Research, 5300 Chiron Way, Emeryville, CA 94608, USA.
2026 South Lincoln Avenue, Spokane, WA 99203, USA.
311 Preakness Court, Walnut Creek, CA 94597, USA.
Oppilan Pharma, Ltd., 332 Encinitas Blvd., Encinitas, CA 92024, USA.
2375 Cowper Street, Palo Alto, CA 94301, USA.
Arcus Biosciences, 3928 Point Eden Way, Hayward, CA 94545, USA.
3305 Cydonia Ct., Dublin, CA 94568, USA.
Rain Therapeutics Inc., 8000 Jarvis Avenue, Suite 204, Newark, CA 94560, USA.
Takeda San Diego Inc., 10410 Science Center Dr., San Diego, CA 92121, USA.

Glycogen synthase kinase-3 plays an essential role in multiple biochemical pathways in the cell, particularly in regards to energy regulation. As such, Glycogen synthase kinase-3 is an attractive target for pharmacological intervention in a variety of disease states, particularly non-insulin dependent diabetes mellitus. However, due to homology with other crucial kinases, such as the cyclin-dependent protein kinase CDC2, developing compounds that are both potent and selective is challenging. A novel series of derivatives of 5-nitro-N2-(2-(pyridine-2ylamino)ethyl)pyridine-2,6-diamine were synthesized and have been shown to potently inhibit glycogen synthase kinase-3 (GSK3). Potency in the low nanomolar range was obtained along with remarkable selectivity. The compounds activate glycogen synthase in insulin receptor-expressing CHO-IR cells and in primary rat hepatocytes, and have acceptable pharmacokinetics and pharmacodynamics to allow for oral dosing. The X-ray co-crystal structure of human GSK3-β in complex with compound 2 is reported and provides insights into the structural determinants of the series responsible for its potency and selectivity.

中文翻译：

发现和优化新型吡啶作为高效和选择性糖原合酶激酶3抑制剂。

糖原合酶激酶3在细胞的多个生化途径中起着至关重要的作用，特别是在能量调节方面。这样，糖原合酶激酶-3是在多种疾病状态，特别是非胰岛素依赖性糖尿病中的药理干预的有吸引力的靶标。但是，由于与其他关键激酶（如细胞周期蛋白依赖性蛋白激酶CDC2）的同源性，开发既有效又具有选择性的化合物具有挑战性。合成了一系列新的5-硝基-N2-（2-（吡啶-2-基氨基）乙基）吡啶-2,6-二胺衍生物，并已显示出可有效抑制糖原合酶激酶-3（GSK3）。在低纳摩尔范围内获得了出色的选择性。该化合物在表达胰岛素受体的CHO-IR细胞和原代大鼠肝细胞中激活糖原合酶，并具有可接受的药代动力学和药效学，可以口服给药。报告了人GSK3-β与化合物2形成复合物的X射线共晶体结构，该结构提供了有关其效力和选择性的系列结构决定因素的见解。

更新日期：2019-12-23

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