The design of orally bioavailable 2, 5-diketopiperazine oxytocin antagonists: from concept to clinical candidate for premature labor

2009 ◽  
Vol 31 (4) ◽  
pp. 576-604 ◽  
Author(s):  
Alan D. Borthwick ◽  
John Liddle
Keyword(s):  
Premature Labor ◽  
Oxytocin Antagonists ◽  
Orally Bioavailable ◽  
Clinical Candidate

2,5-Diketopiperazines as Potent, Selective, and Orally Bioavailable Oxytocin Antagonists. 2. Synthesis, Chirality, and Pharmacokinetics

2005 ◽  
Vol 48 (22) ◽  
pp. 6956-6969 ◽  
Author(s):  
Alan D. Borthwick ◽  
Dave E. Davies ◽  
Anne M. Exall ◽  
David G. Livermore ◽  
Steve L. Sollis ◽  
...  
Keyword(s):  
Oxytocin Antagonists ◽  
Orally Bioavailable

Abstract 3650: Discovery of the clinical candidate AZD9496: a potent and orally bioavailable selective estrogen receptor downregulator and antagonist

2015 ◽  
Author(s):  
Chris De Savi ◽  
Robert H. Bradbury ◽  
Alfred A. Rabow ◽  
Richard A. Norman ◽  
David Buttar ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Orally Bioavailable ◽  
Clinical Candidate

scholarly journals 5-(4,6-Dimorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine (PQR309), a Potent, Brain-Penetrant, Orally Bioavailable, Pan-Class I PI3K/mTOR Inhibitor as Clinical Candidate in Oncology

2017 ◽  
Vol 60 (17) ◽  
pp. 7524-7538 ◽  
Author(s):  
Florent Beaufils ◽  
Natasa Cmiljanovic ◽  
Vladimir Cmiljanovic ◽  
Thomas Bohnacker ◽  
Anna Melone ◽  
...  
Keyword(s):  
Mtor Inhibitor ◽  
Class I ◽  
Orally Bioavailable ◽  
Clinical Candidate

scholarly journals Discovery of PF-5190457, a Potent, Selective, and Orally Bioavailable Ghrelin Receptor Inverse Agonist Clinical Candidate

2014 ◽  
Vol 5 (5) ◽  
pp. 474-479 ◽  
Author(s):  
Samit K. Bhattacharya ◽  
Kim Andrews ◽  
Ramsay Beveridge ◽  
Kimberly O. Cameron ◽  
Chiliu Chen ◽  
...  
Keyword(s):  
Inverse Agonist ◽  
Ghrelin Receptor ◽  
Orally Bioavailable ◽  
Receptor Inverse Agonist ◽  
Clinical Candidate

Pyridyl-2,5-Diketopiperazines as Potent, Selective, and Orally Bioavailable Oxytocin Antagonists: Synthesis, Pharmacokinetics, and In Vivo Potency

2012 ◽  
Vol 55 (2) ◽  
pp. 783-796 ◽  
Author(s):  
Alan D. Borthwick ◽  
John Liddle ◽  
Dave E. Davies ◽  
Anne M. Exall ◽  
Christopher Hamlett ◽  
...  
Keyword(s):  
Oxytocin Antagonists ◽  
Orally Bioavailable

Preclinical evaluation of TQB3602, a small molecule proteasome inhibitor clinical candidate.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e20546-e20546
Author(s):  
Xiquan Zhang ◽  
Ling Yang ◽  
Xin Tian ◽  
Lihua He ◽  
Jian Xiong ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Line ◽  
Small Molecule ◽  
Boronic Acid ◽  
Proteasome Inhibitor ◽  
Antitumor Efficacy ◽  
20S Proteasome ◽  
Orally Bioavailable ◽  
Clinical Candidate

e20546 Background: Proteasome inhibitors, selectively inhibit the activity of proteasome in ubiquitin proteasome system, together with immunomodulatory drugs formed the basis of many treatment regimens for multiple myeloma in first-line therapy as well as for the treatment of relapsed disease. Bortezomib (Velcade), the first approved therapeutic proteasome inhibitor with a unique boronic acid as warhead, limited by its requirement for parenteral administration (intravenous or subcutaneous). The 2nd generation boronic acid – orally bioavailable Ixazomib (Ninlaro) was approved in 2015 by FDA greatly improved patient’s compliance. However, its adverse effect remained an issue in clinical application. The purpose of this study is to investigate the in vitro and in vivo antitumor activity of TQB3602, a novel orally bioavailable small molecule proteasome inhibitor, in preclinical models of multiple myeloma. Methods: The enzyme inhibition and anti-proliferative activity of TQB3602 was evaluated in 20S proteasome and MM.1S cell line. Oral administration of TQB3602 at 3 doses was used to evaluate the in vivo anti-tumor activity in MM.1S multiple myeloma xenograft (CDX) models. Results: TQB3602 displayed potent kinase inhibiting activity for 20S proteasome enzyme with IC50 15.3 nM. TQB3602 inhibited cell proliferation in MM.1S multiple myeloma cell line with IC50 10.1 nM. In the MM.1S multiple myeloma CB-17 CDX model, TQB3602 showed antitumor efficacy with TGI > 100% @7 mpk, BIW (tumor can’t be measured from day 17). Conclusions: We have identified a novel potent proteasome inhibitor TQB3602. Preclinical studies showed antitumor efficacy of TQB3602 in MM.1S multiple myeloma model. TQB3602 represents a promising clinical candidate for treating multiple myeloma and the First-in-human trial is expected in the middle of 2020.

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