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

2,5-Diketopiperazines as Potent, Selective, and Orally Bioavailable Oxytocin Antagonists. 3. Synthesis, Pharmacokinetics, and in Vivo Potency

2006 ◽  
Vol 49 (14) ◽  
pp. 4159-4170 ◽  
Author(s):  
Alan D. Borthwick ◽  
Dave E. Davies ◽  
Anne M. Exall ◽  
Richard J. D. Hatley ◽  
Jennifer A. Hughes ◽  
...  
Keyword(s):  
Oxytocin Antagonists ◽  
Orally Bioavailable

scholarly journals TTI-281, an Orally Bioavailable Bromodomain and Extraterminal Domain (BET) Inhibitor, Is a Promising Candidate for the Treatment of Multiple Myeloma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2095-2095
Author(s):  
Zezhou Wang ◽  
Jaehyun Choi ◽  
Peter Dove ◽  
Chunlei Wang ◽  
Aaron D. Schimmer ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Therapeutic Agents ◽  
Vehicle Control ◽  
Advisory Committees ◽  
Bet Inhibitor ◽  
Low Toxicity ◽  
Orally Bioavailable

Abstract Although recent advances in the development of multiple myeloma (MM) therapies such as proteasome inhibitors and immunomodulatory agents have improved patient outcomes, MM remains incurable. Additional therapeutic agents with high efficacy, low toxicity and the convenience of oral administration are in high demand. BET inhibitors, such as JQ-1, have been considered as potential therapeutic agents for MM. In the present study, we report that TTI-281, an orally bioavailable BET inhibitor, displays anti-MM activity with a low toxicity profile in preclinical studies. First, TTI-281 was tested for binding and anti-tumor activity in vitro. BROMOscan and AlphaScreen assays demonstrated that TTI-281 bound to bromodomains of BRD2/BRD3/BRD4 with Kd values less than 10 nM. In MTS assays, TTI-281 inhibited the growth of MM cell lines (MM.1s, NCIH929, and RPMI-8826) with cell growth-inhibition (IC50) values less than 300 nM. Next, in vitro ADME screening and in vivo PK studies were conducted. Permeability assays using murine gastrointestinal epithelial cells indicated that TTI-281 had good permeability with little efflux liability (efflux ratio <1), suggesting favorable properties for oral absorption. Indeed, TTI-281 displayed excellent oral bioavailability in both mice and rats (93.1% and 91.8%, respectively). In addition, TTI-281 did not interfere with the metabolism of representative CYP isozyme substrates at concentrations up to 50 μM in pooled human liver microsomes. Data also suggested minimal potential for drug-drug interactions, allowing for the possible combination with first-line therapy to improve therapeutic and survival outcomes. Finally, TTI-281 was tested for anti-myeloma efficacy and tolerability in vivo. NOD-SCID mice (n=10/group) subcutaneously engrafted with the human myeloma cell line MM.1S were treated orally once daily for 21 days with different doses of TTI-281, vehicle control or the benchmark drug carfilzomib. TTI-281 reduced tumor growth in a dose-dependent manner in this MM xenograft model. At 30 mg/kg/day, TTI-281 led to a statistically significant decrease in tumor growth compared with the vehicle control and carfilzomib (reduced tumor volume: 67% after TTI-281 treatment vs 33% after carfilzomib treatment, p<0.0003). Furthermore, TTI-281 treatment was well tolerated, with no effect on body weight or other obvious toxicity. In summary, our preclinical data suggest that the orally available BET inhibitor TTI-281 has an excellent efficacy and safety profile, highlighting its potential as a promising drug candidate for myeloma therapy. Disclosures Wang: Trillium Therapeutics: Employment, Patents & Royalties. Choi:Trillium Therapeutics: Employment. Dove:Trillium Therapeutics: Employment, Patents & Royalties. Wang:Trillium Therapeutics: Employment. Schimmer:Novartis: Honoraria. Petrova:Trillium Therapeutics Inc: Employment, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Uger:Trillium Therapeutics: Employment, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Slassi:Trillium Therapeutics: Employment, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties.

SOMCL-863, a novel, selective and orally bioavailable small-molecule c-Met inhibitor, exhibits antitumor activity both in vitro and in vivo

2014 ◽  
Vol 351 (1) ◽  
pp. 143-150 ◽  
Author(s):  
Lu Wang ◽  
Jing Ai ◽  
Yanyan Shen ◽  
Haotian Zhang ◽  
Xia Peng ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Small Molecule ◽  
Met Inhibitor ◽  
Orally Bioavailable

scholarly journals Identification and in vivo Efficacy Assessment of Approved Orally Bioavailable Human Host Protein-Targeting Drugs With Broad Anti-influenza A Activity

2019 ◽  
Vol 10 ◽  
Author(s):  
Theresa Enkirch ◽  
Svenja Sauber ◽  
Danielle E. Anderson ◽  
Esther S. Gan ◽  
Dimitar Kenanov ◽  
...  
Keyword(s):  
Influenza A ◽  
Protein Targeting ◽  
Host Protein ◽  
In Vivo Efficacy ◽  
Human Host ◽  
Efficacy Assessment ◽  
Orally Bioavailable

scholarly journals A Duplexed High-Throughput Screen to Identify Allosteric Modulators of the Glucagon-Like Peptide 1 and Glucagon Receptors

2014 ◽  
Vol 19 (6) ◽  
pp. 847-858 ◽  
Author(s):  
Lindsey C. Morris ◽  
Emily L. Days ◽  
Maxine Turney ◽  
Dehui Mi ◽  
Craig W. Lindsley ◽  
...  
Keyword(s):  
High Throughput ◽  
Allosteric Modulators ◽  
High Throughput Screen ◽  
Glucagon Receptor ◽  
Three Phase ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Orally Bioavailable ◽  
Glucagon Receptors

Injectable, degradation-resistant peptide agonists for the glucagon-like peptide 1 (GLP-1) receptor (GLP-1R), such as exenatide and liraglutide, activate the GLP-1R via a complex orthosteric-binding site and are effective therapeutics for glycemic control in type 2 diabetes. Orally bioavailable orthosteric small-molecule agonists are unlikely to be developed, whereas positive allosteric modulators (PAMs) may offer an improved therapeutic profile. We hypothesize that allosteric modulators of the GLP-1R would increase the potency and efficacy of native GLP-1 in a spatial and temporally preserved manner and/or may improve efficacy or side effects of injectable analogs. We report the design, optimization, and initial results of a duplexed high-throughput screen in which cell lines overexpressing either the GLP-1R or the glucagon receptor were coplated, loaded with a calcium-sensitive dye, and probed in a three-phase assay to identify agonists, antagonists, and potentiators of GLP-1, and potentiators of glucagon. 175,000 compounds were initially screened, and progression through secondary assays yielded 98 compounds with a variety of activities at the GLP-1R. Here, we describe five compounds possessing different patterns of modulation of the GLP-1R. These data uncover PAMs that may offer a drug-development pathway to enhancing in vivo efficacy of both endogenous GLP-1 and peptide analogs.

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 4413: STX140 is an orally bioavailable microtubule targeting agent with no associated peripheral neuropathy and potent anti-metastasis efficacy in vivo

2010 ◽  
Author(s):  
Simon P. Newman ◽  
Paul A. Foster ◽  
Joanna M. Day ◽  
Mathew P. Leese ◽  
Barry VL Potter ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Orally Bioavailable
Sign in / Sign up

Export Citation Format

Share Document