Literature DB >> 24900655

[3a,4]-Dihydropyrazolo[1,5a]pyrimidines: Novel, Potent, and Selective Phosphatidylinositol-3-kinase β Inhibitors.

Hongyi Yu1, Michael L Moore1, Karl Erhard1, Mary Ann Hardwicke1, Hong Lin1, Juan I Luengo1, Jeanelle McSurdy-Freed1, Ramona Plant1, Junya Qu1, Kaushik Raha1, Cynthia M Rominger1, Michael D Schaber1, Michael D Spengler1, Ralph A Rivero1.   

Abstract

A series of novel [3a,4]dihydropyrazolo[1,5a]pyrimidines were identified, which were highly potent and selective inhibitors of PI3Kβ. The template afforded the opportunity to develop novel SAR for both the hinge-binding (R3) and back-pocket (R4) substitutents. While cellular potency was relatively modest due to high protein binding, the series displayed low clearance in rat, mouse, and monkey.

Entities:  

Keywords:  PI3K-β inhibitor; PTEN-null; phosphatidylinositol-3-kinase; pyrazolopyrimidine; structure−activity relationship

Year:  2013        PMID： 24900655      PMCID： PMC4027147          DOI： 10.1021/ml300330m

Source DB:  PubMed          Journal:  ACS Med Chem Lett        ISSN： 1948-5875            Impact factor:   4.345


  20 in total

1.  A constitutively activated form of the p110beta isoform of PI3-kinase induces prostatic intraepithelial neoplasia in mice.

Authors:  Sang Hyun Lee; George Poulogiannis; Saumyadipta Pyne; Shidong Jia; Lihua Zou; Sabina Signoretti; Massimo Loda; Lewis Clayton Cantley; Thomas M Roberts
Journal:  Proc Natl Acad Sci U S A       Date:  2010-06-01       Impact factor: 11.205

Review 2.  The effect of plasma protein binding on in vivo efficacy: misconceptions in drug discovery.

Authors:  Dennis A Smith; Li Di; Edward H Kerns
Journal:  Nat Rev Drug Discov       Date:  2010-12       Impact factor: 84.694

Review 3.  Targeting PI3K signaling as a therapeutic approach for colorectal cancer.

Authors:  Jing Zhang; Thomas M Roberts; Ramesh A Shivdasani
Journal:  Gastroenterology       Date:  2011-07       Impact factor: 22.682

4.  Rational Design, Synthesis, and SAR of a Novel Thiazolopyrimidinone Series of Selective PI3K-beta Inhibitors.

Authors:  Hong Lin; Mark J Schulz; Ren Xie; Jin Zeng; Juan I Luengo; Michael D Squire; Rosanna Tedesco; Junya Qu; Karl Erhard; James F Mack; Kaushik Raha; Ramona Plant; Cynthia M Rominger; Jennifer L Ariazi; Christian S Sherk; Michael D Schaber; Jeanelle McSurdy-Freed; Michael D Spengler; Charles B Davis; Mary Ann Hardwicke; Ralph A Rivero
Journal:  ACS Med Chem Lett       Date:  2012-05-29       Impact factor: 4.345

Review 5.  Oncogenic PI3K and its role in cancer.

Authors:  Yardena Samuels; Kajsa Ericson
Journal:  Curr Opin Oncol       Date:  2006-01       Impact factor: 3.645

6.  The catalytic subunit of phosphoinositide 3-kinase: requirements for oncogenicity.

Authors:  M Aoki; C Schetter; M Himly; O Batista; H W Chang; P K Vogt
Journal:  J Biol Chem       Date:  2000-03-03       Impact factor: 5.157

Review 7.  Targeting PI3K signalling in cancer: opportunities, challenges and limitations.

Authors:  Jeffrey A Engelman
Journal:  Nat Rev Cancer       Date:  2009-08       Impact factor: 60.716

8.  Essential roles of PI(3)K-p110beta in cell growth, metabolism and tumorigenesis.

Authors:  Shidong Jia; Zhenning Liu; Sen Zhang; Pixu Liu; Lei Zhang; Sang Hyun Lee; Jing Zhang; Sabina Signoretti; Massimo Loda; Thomas M Roberts; Jean J Zhao
Journal:  Nature       Date:  2008-06-25       Impact factor: 49.962

9.  Pd-catalyzed amidation of aryl chlorides using monodentate biaryl phosphine ligands: a kinetic, computational, and synthetic investigation.

Authors:  Takashi Ikawa; Timothy E Barder; Mark R Biscoe; Stephen L Buchwald
Journal:  J Am Chem Soc       Date:  2007-10-05       Impact factor: 15.419

Review 10.  A beta version of life: p110β takes center stage.

Authors:  Hashem A Dbouk; Jonathan M Backer
Journal:  Oncotarget       Date:  2010-12
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  1 in total

1.  Discovery of an Atropisomeric PI3Kβ Selective Inhibitor through Optimization of the Hinge Binding Motif.

Authors:  Stephane Perreault; Fatima Arjmand; Jayaraman Chandrasekhar; Jia Hao; Kathleen S Keegan; David Koditek; Eve-Irene Lepist; Clinton K Matson; Mary E McGrath; Leena Patel; Kassandra Sedillo; Joseph Therrien; Nicholas A Till; Adrian Tomkinson; Jennifer Treiberg; Yelena Zherebina; Gary Phillips
Journal:  ACS Med Chem Lett       Date:  2020-04-13       Impact factor: 4.345
  1 in total

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