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DMPK optimization

Michael R Wood, Meredith J Noetzel, Michael S Poslusney, Bruce J Melancon, James C Tarr, Atin Lamsal, Sichen Chang, Vincent B Luscombe, Rebecca L Weiner, Hyekyung P Cho, Michael Bubser, Carrie K Jones, Colleen M Niswender, Michael W Wood, Darren W Engers, Nicholas J Brandon, Mark E Duggan, P Jeffrey Conn, Thomas M Bridges, Craig W Lindsley
This letter describes the chemical optimization of a novel series of M4 positive allosteric modulators (PAMs) based on a 5-amino-thieno[2,3-c]pyridazine core, developed via iterative parallel synthesis, and culminating in the highly utilized rodent in vivo tool compound, VU0467154 (5). This is the first report of the optimization campaign (SAR and DMPK profiling) that led to the discovery of VU0467154, and details all of the challenges faced in allosteric modulator programs (steep SAR, species differences in PAM pharmacology and subtle structural changes affecting CNS penetration)...
January 15, 2017: Bioorganic & Medicinal Chemistry Letters
Andrew M Haidle, Kaleen K Childers, Anna A Zabierek, Jason D Katz, James P Jewell, Yongquan Hou, Michael D Altman, Alexander Szewczak, Dapeng Chen, Andreas Harsch, Mansuo Hayashi, Lee Warren, Michael Hutton, Hugh Nuthall, Matt G Stanton, Ian W Davies, Ben Munoz, Alan Northrup
Attempts to optimize pharmacokinetic properties in a promising series of pyrrolopyrimidinone MARK inhibitors for the treatment of Alzheimer's disease are described. A focus on physical properties and ligand efficiency while prosecuting this series afforded key tool compounds that revealed a large discrepancy in the rat in vitro-in vivo DMPK (Drug Metabolism/Pharmacokinetics) correlation. These differences prompted an in vivo rat disposition study employing a radiolabeled representative of the series, and the results from this experiment justified the termination of any further optimization efforts...
January 1, 2017: Bioorganic & Medicinal Chemistry Letters
Kayla J Temple, Matthew T Duvernay, Jae G Maeng, Anna L Blobaum, Shaun R Stauffer, Heidi E Hamm, Craig W Lindsley
This letter describes the further deconstruction of the known PAR4 inhibitor chemotypes (MWs 490-525 and with high plasma protein binding) to identify a minimum PAR4 pharmacophore devoid of metabolic liabilities and improved properties. This exercise identified a greatly simplified 2-methoxy-6-arylimidazo[2,1-b][1,3,4]thiadiazole scaffold that afforded nanomolar inhibition of both activating peptide and γ-thrombin mediated PAR4 stimulation, while reducing both molecular weight and the number of hydrogen bond donors/acceptors by ∼50%...
November 15, 2016: Bioorganic & Medicinal Chemistry Letters
Tony Fröhlich, Svetlana B Tsogoeva
In order to overcome one of the greatest challenges in malaria treatment, drug resistance, new drug candidates are urgently needed, which should preferably act via novel mechanisms. Successful optimization of a phenotypic screening hit based on a quinoline-4-carboxamide derivative resulted in the highly promising lead structure 4, which according to the Medicines for Malaria Venture (MMV) met the efficacy and drug metabolism and pharmacokinetics (DMPK) requirements for a malaria drug target candidate and consequently was selected for preclinical development...
November 10, 2016: Journal of Medicinal Chemistry
Mulias Lian, Hai-Yang Law, Caroline G Lee, Samuel S Chong
BACKGROUND: DMPK CTG-repeat expansions that cause myotonic dystrophy type 1 (DM1) can be detected more rapidly, cost-effectively, and simply by combining triplet-primed PCR (TP-PCR) with melting curve analysis (MCA). We undertook a detailed technical validation study to define the optimal operational parameters for performing bidirectional TP-PCR MCA assays. METHODS: We determined the assays' analytic specificity and sensitivity, assessed the effect of reaction volumes, DNA diluents, and common contaminants on melt peak temperature, determined the assays' sensitivity in detecting low-level mosaicism for repeat expansion, and evaluated their performance on two real-time PCR platforms...
October 8, 2016: Expert Review of Molecular Diagnostics
Beatriz Baragaña, Neil R Norcross, Caroline Wilson, Achim Porzelle, Irene Hallyburton, Raffaella Grimaldi, Maria Osuna-Cabello, Suzanne Norval, Jennifer Riley, Laste Stojanovski, Frederick R C Simeons, Paul G Wyatt, Michael J Delves, Stephan Meister, Sandra Duffy, Vicky M Avery, Elizabeth A Winzeler, Robert E Sinden, Sergio Wittlin, Julie A Frearson, David W Gray, Alan H Fairlamb, David Waterson, Simon F Campbell, Paul Willis, Kevin D Read, Ian H Gilbert
The antiplasmodial activity, DMPK properties, and efficacy of a series of quinoline-4-carboxamides are described. This series was identified from a phenotypic screen against the blood stage of Plasmodium falciparum (3D7) and displayed moderate potency but with suboptimal physicochemical properties and poor microsomal stability. The screening hit (1, EC50 = 120 nM) was optimized to lead molecules with low nanomolar in vitro potency. Improvement of the pharmacokinetic profile led to several compounds showing excellent oral efficacy in the P...
November 10, 2016: Journal of Medicinal Chemistry
Christoph Boss, Hamed Aissaoui, Nathalie Amaral, Aude Bauer, Stephanie Bazire, Christoph Binkert, Reto Brun, Cédric Bürki, Claire-Lise Ciana, Olivier Corminboeuf, Stephane Delahaye, Claire Dollinger, Christoph Fischli, Walter Fischli, Alexandre Flock, Marie-Céline Frantz, Malory Girault, Corinna Grisostomi, Astrid Friedli, Bibia Heidmann, Claire Hinder, Gael Jacob, Amelie Le Bihan, Sophie Malrieu, Saskia Mamzed, Aurelien Merot, Solange Meyer, Sabrina Peixoto, Nolwenn Petit, Romain Siegrist, Julien Trollux, Thomas Weller, Sergio Wittlin
More than 40 % of the world's population is at risk of being infected with malaria. Most malaria cases occur in the countries of sub-Saharan Africa, Central and South America, and Asia. Resistance to standard therapy, including artemisinin combinations, is increasing. There is an urgent need for novel antimalarials with new mechanisms of action. In a phenotypic screen, we identified a series of phenylalanine-based compounds that exhibit antimalarial activity via a new and yet unknown mechanism of action. Our optimization efforts culminated in the selection of ACT-451840 [(S,E)-N-(4-(4-acetylpiperazin-1-yl)benzyl)-3-(4-(tert-butyl)phenyl)-N-(1-(4-(4-cyanobenzyl)piperazin-1-yl)-1-oxo-3-phenylpropan-2-yl)acrylamide] for clinical development...
September 20, 2016: ChemMedChem
Rocco D Gogliotti, Darren W Engers, Pedro M Garcia-Barrantes, Joseph D Panarese, Patrick R Gentry, Anna L Blobaum, Ryan D Morrison, J Scott Daniels, Analisa D Thompson, Carrie K Jones, P Jeffrey Conn, Colleen M Niswender, Craig W Lindsley, Corey R Hopkins
This letter describes the further chemical optimization of the picolinamide-derived family of mGlu4 PAMs wherein we identified a 3-amino substituent to the picolinamide warhead that engendered potency, CNS penetration and in vivo efficacy. From this optimization campaign, VU0477886 emerged as a potent (EC50=95nM, 89% Glu Max) mGlu4 PAM with an attractive DMPK profile (brain:plasma Kp=1.3), rat CLp=4.0mL/min/kg, t1/2=3.7h) and robust efficacy in our standard preclinical Parkinson's disease model, haloperidol-induced catalepsy (HIC)...
June 15, 2016: Bioorganic & Medicinal Chemistry Letters
Craig Fraser, John C Dawson, Reece Dowling, Douglas R Houston, Jason T Weiss, Alison F Munro, Morwenna Muir, Lea Harrington, Scott P Webster, Margaret C Frame, Valerie G Brunton, E Elizabeth Patton, Neil O Carragher, Asier Unciti-Broceta
Novel pyrazolopyrimidines displaying high potency and selectivity toward SRC family kinases have been developed by combining ligand-based design and phenotypic screening in an iterative manner. Compounds were derived from the promiscuous kinase inhibitor PP1 to search for analogs that could potentially target a broad spectrum of kinases involved in cancer. Phenotypic screening against MCF7 mammary adenocarcinoma cells generated target-agnostic structure-activity relationships that biased subsequent designs toward breast cancer treatment rather than to a particular target...
May 26, 2016: Journal of Medicinal Chemistry
Pedro M Garcia-Barrantes, Hyekyung P Cho, Anna L Blobaum, Colleen M Niswender, P Jeffrey Conn, Craig W Lindsley
This Letter describes the further lead optimization of the VU0486321 series of mGlu1 positive allosteric modulators (PAMs), focused on addressing the recurrent issue of plasma instability of the phthalimide moiety. Here, we evaluated a number of phthalimide bioisosteres, and ultimately identified isoindolinones as the ideal replacement that effectively address plasma instability, while maintaining acceptable mGlu1 PAM potency, DMPK profile, CNS penetration and mGluR selectivity.
April 15, 2016: Bioorganic & Medicinal Chemistry Letters
Pedro M Garcia-Barrantes, Hyekyung P Cho, Adam M Metts, Anna L Blobaum, Colleen M Niswender, P Jeffrey Conn, Craig W Lindsley
This Letter describes the further lead optimization of the VU0486321 series of mGlu1 positive allosteric modulators (PAMs), driven by recent genetic data linking loss of function GRM1 to schizophrenia. Steep and caveat-laden SAR plagues the series, but ultimately potent mGlu1 PAMs (EC50s ∼5 nM) have resulted with good DMPK properties (low intrinsic clearance, clean CYP profile, modest Fu) and CNS penetration (Kps 0.25-0.97), along with up to >450-fold selectivity versus mGlu4 and mGlu5.
February 1, 2016: Bioorganic & Medicinal Chemistry Letters
Anna-Karin Sohlenius-Sternbeck, Juliette Janson, Johan Bylund, Pawel Baranczewski, Anna Breitholtz-Emanuelsson, Yin Hu, Carrie Tsoi, Anders Lindgren, Olle Gissberg, Tjerk Bueters, Sveinn Briem, Sanja Juric, Jenny Johansson, Margareta Bergh, Janet Hoogstraate
BACKGROUND: The disposition of a drug is dependent on interactions between the body and the drug, its molecular properties and the physical and biological barriers presented in the body. In order for a drug to have a desired pharmacological effect it has to have the right properties to be able to reach the target site in sufficient concentration. This review details how drug metabolism and pharmacokinetics (DMPK) and physicochemical deliveries played an important role in data interpretation and compound optimization at AstraZeneca R&D in Södertälje, Sweden...
2016: Current Drug Metabolism
Yan-Xin Meng, Hong-Rui Shen, Zhe Zhao, Qi Bing, Nan Li, Jing Hu
CONTEXT: Myotonic dystrophies (DMs) are a group of autosomal dominant neuromuscular disorders which are caused by large CTG/CCTG-repeat expansions in untranslated regions of DMPK/ZNF9 gene. The "phenotypic overlap" in DMs creates complication in distinguishing patients with DM1 from patients with DM2 and underscores the need for these patients to undergo genetic test; therefore, detection and accurate sizing of the CTG/CCTG-repeat expansions are necessary. Templates with long CTG/CCTG tandem repeats are difficult to amplify by convention PCR...
2015: Annals of Clinical and Laboratory Science
Heesang Lee, Yujin Park, Jiyeong Jo, Sangwhan In, Yonghoon Park, Eunmi Kim, Jaesung Pyo, Sanggil Choe
Dried Blood Spot (DBS) has been used a blood extraction method for inherited metabolic disorder screening since 1960s. With introduction of LC-MS/MS, not only DBS could be used to analysis drugs in small blood volume, but in various fields, such as toxicology, drug therapeutic monitoring, drug diagnostic screening, and illicit drugs. In toxicology field, many drugs (e.g. benzodiazepines, acetaminophen, small molecule drugs) have been tested with DBS. Compared with earlier blood extraction methods (SPE and LLE), DBS has lots of advantages; lower blood volume (less than 50μL), shorter analysis time caused by a more concise analysis procedure and lower cost...
October 2015: Forensic Science International
Da-Cheng Hao, Guang-Bo Ge, Pei-Gen Xiao, Ping Wang, Ling Yang
The wide-reaching distributed angiosperm family Ranunculaceae has approximately 2200 species in around 60 genera. Chemical components of this family include several representative groups: benzylisoquinoline alkaloid (BIA), ranunculin, triterpenoid saponin and diterpene alkaloid, etc. Their extensive clinical utility has been validated by traditional uses of thousands of years and current evidence-based medicine studies. Drug metabolism and pharmacokinetic (DMPK) studies of plant-based natural products are an indispensable part of comprehensive medicinal plant exploration, which could facilitate conservation and sustainable utilization of Ranunculaceae pharmaceutical resources, as well as new chemical entity development with improved DMPK parameters...
2015: Current Drug Metabolism
Thorsten Oost, Armin Heckel, Jörg T Kley, Thorsten Lehmann, Stephan Müller, Gerald J Roth, Klaus Rudolf, Kirsten Arndt, Ralph Budzinski, Martin Lenter, Ralf R H Lotz, Gerd-Michael Maier, Michael Markert, Leo Thomas, Dirk Stenkamp
Although overweight and obesity are highly prevalent conditions, options to treat them are still very limited. As part of our search for safe and effective MCH-R1 antagonists for the treatment of obesity, two series of pyridones and pyridazinones were evaluated. Optimization was aimed at improving DMPK properties by increasing metabolic stability and improving the safety profile by reducing inhibition of the hERG channel and reducing the potential to induce phospholipidosis. Steric shielding of a labile keto moiety with an ortho-methyl group and fine-tuning of the polarity in several parts of the molecule resulted in BI 186908 (11 g), a potent and selective MCH-R1 antagonist with favorable DMPK and CMC properties...
August 15, 2015: Bioorganic & Medicinal Chemistry Letters
Michael A Letavic, Pascal Bonaventure, Nicholas I Carruthers, Christine Dugovic, Tatiana Koudriakova, Brian Lord, Timothy W Lovenberg, Kiev S Ly, Neelakandha S Mani, Diane Nepomuceno, Daniel J Pippel, Michele Rizzolio, Jonathan E Shelton, Chandra R Shah, Brock T Shireman, Lana K Young, Sujin Yun
The preclinical characterization of novel octahydropyrrolo[3,4-c]pyrroles that are potent and selective orexin-2 antagonists is described. Optimization of physicochemical and DMPK properties led to the discovery of compounds with tissue distribution and duration of action suitable for evaluation in the treatment of primary insomnia. These selective orexin-2 antagonists are proven to promote sleep in rats, and this work ultimately led to the identification of a compound that progressed into human clinical trials for the treatment of primary insomnia...
July 23, 2015: Journal of Medicinal Chemistry
Timothy Senter, Rocco D Gogliotti, Changho Han, Charles W Locuson, Ryan Morrison, J Scott Daniels, Tomasz Cierpicki, Jolanta Grembecka, Craig W Lindsley, Shaun R Stauffer
A series of substituted hydroxymethyl piperidine small molecule inhibitors of the protein-protein interaction between menin and mixed lineage leukemia 1 (MLL1) are described. Initial members of the series showed good inhibitory disruption of the menin-MLL1 interaction but demonstrated poor physicochemical and DMPK properties. Utilizing a structure-guided and iterative optimization approach key substituents were optimized leading to inhibitors with cell-based activity, improved in vitro DMPK parameters, and improved half-lives in rodent PK studies leading to MLPCN probe ML399...
July 1, 2015: Bioorganic & Medicinal Chemistry Letters
Ke Zheng, Chul Min Park, Sarah Iqbal, Pamela Hernandez, HaJeung Park, Philip V LoGrasso, Yangbo Feng
A novel series of 2-aminopyridopyrimidinone based JNK (c-jun N-terminal kinase) inhibitors were discovered and developed. Structure-activity relationships (SARs) were systematically developed utilizing biochemical and cell based assays and in vitro and in vivo drug metabolism and pharmacokinetic (DMPK) studies. Through the optimization of lead compound 1, several potent and selective JNK inhibitors with high oral bioavailability were developed. Inhibitor 13 was a potent JNK3 inhibitor (IC50 = 15 nM), had high selectivity against p38 (IC50 > 10 μM), had high potency in functional cell based assays, and had high stability in human liver microsome (t 1/2 = 76 min), a clean CYP-450 inhibition profile, and excellent oral bioavailability (%F = 87)...
April 9, 2015: ACS Medicinal Chemistry Letters
Mulias Lian, Indhu-Shree Rajan-Babu, Kunal Singh, Caroline G Lee, Hai-Yang Law, Samuel S Chong
Instability and expansion of the DMPK CTG repeat cause myotonic dystrophy type 1 (DM1), the most common adult-onset neuromuscular disorder. Overlapping clinical features between DM1 and other myotonic disorders necessitate molecular confirmation for definitive diagnosis. Preconception screening could improve reproductive planning especially in DM1-affected women, who show diminished ovarian reserve and unfavorable in vitro fertilization-preimplantation genetic diagnosis outcome. We optimized triplet-primed PCR and melting curve analysis on 17 DNAs from DM1-affected/unaffected cell lines...
March 2015: Journal of Molecular Diagnostics: JMD
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