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DMPK optimization

Ling Song, Yi Zhang, Ji Jiang, Shuang Ren, Li Chen, Dongyang Liu, Xijing Chen, Pei Hu
AIM: The objective of this study was to develop a physiologically based pharmacokinetic (PBPK) model for sinogliatin (HMS-5552, dorzagliatin) by integrating allometric scaling (AS), in vitro to in vivo exploration (IVIVE), and steady-state concentration-mean residence time (Css -MRT) methods and to provide mechanistic insight into its pharmacokinetic properties in humans. METHODS: Human major pharmacokinetic parameters were analyzed using AS, IVIVE, and Css -MRT methods with available preclinical in vitro and in vivo data to understand sinogliatin drug metabolism and pharmacokinetic (DMPK) characteristics and underlying mechanisms...
April 6, 2018: Clinical Pharmacokinetics
Ulrich Lücking, Arne Scholz, Philip Lienau, Gerhard Siemeister, Dirk Kosemund, Rolf Bohlmann, Hans Briem, Ildiko Terebesi, Kirstin Meyer, Katja Prelle, Karsten Denner, Ulf Bömer, Martina Schäfer, Knut Eis, Ray Valencia, Stuart Ince, Franz von Nussbaum, Dominik Mumberg, Karl Ziegelbauer, Bert Klebl, Axel Choidas, Peter Nussbaumer, Matthias Baumann, Carsten Schultz-Fademrecht, Gerd Rühter, Jan Eickhoff, Michael Brands
Selective inhibition of exclusively transcription-regulating PTEFb/CDK9 is a promising new approach in cancer therapy. Starting from lead compound BAY-958, lead optimization efforts strictly focusing on kinase selectivity, physicochemical and DMPK properties finally led to the identification of the orally available clinical candidate atuveciclib (BAY 1143572). Structurally characterized by an unusual benzyl sulfoximine group, BAY 1143572 exhibited the best overall profile in vitro and in vivo, including high efficacy and good tolerability in xenograft models in mice and rats...
November 8, 2017: ChemMedChem
Blake R Bewley, Paul K Spearing, Rebecca L Weiner, Vincent B Luscombe, Xiaoyan Zhan, Sichen Chang, Hyekyung P Cho, Alice L Rodriguez, Colleen M Niswender, P Jeffrey Conn, Thomas M Bridges, Darren W Engers, Craig W Lindsley
This Letter details the discovery and subsequent optimization of a novel M4 PAM scaffold based on an 6-fluoro-4-(piperidin-1-yl)quinoline-3-carbonitrile core, which represents a distinct departure from the classical M4 PAM chemotypes. Optimized compounds in this series demonstrated improved M4 PAM potency on both human and rat M4 (4 to 5-fold relative to HTS hit), and displayed attractive physicochemical and DMPK profiles, including good CNS penetration (rat brain:plasma Kp =5.3, Kp,uu =2.4; MDCK-MDR1 (P-gp) ER=1...
September 15, 2017: Bioorganic & Medicinal Chemistry Letters
Da-Cheng Hao, Pei-Gen Xiao
Salvia is the largest genus of family Lamiaceae and has nearly 1000 species. This genus produces several representative phytometabolites, e.g., diterpenoids and phenolic acids. The traditional uses in ethnomedicine and contemporary experimental studies have corroborated extensive therapeutic efficacy of Salvia plants. Drug metabolism and pharmacokinetic (DMPK) studies of Salvia natural products and their derivatives are indispensable in the optimization of lead compounds. New chemical entity with improved DMPK profiles is preferred...
May 30, 2017: Current Drug Metabolism
Bruce J Melancon, Michael R Wood, Meredith J Noetzel, Kellie D Nance, Eileen M Engelberg, Changho Han, Atin Lamsal, Sichen Chang, Hyekyung P Cho, Frank W Byers, Michael Bubser, Carrie K Jones, Colleen M Niswender, Michael W Wood, Darren W Engers, Dedong Wu, Nicholas J Brandon, Mark E Duggan, P Jeffrey Conn, Thomas M Bridges, Craig W Lindsley
This letter describes the further chemical optimization of the 5-amino-thieno[2,3-c]pyridazine series (VU0467154/VU0467485) of M4 positive allosteric modulators (PAMs), developed via iterative parallel synthesis, culminating in the discovery of the non-human primate (NHP) in vivo tool compound, VU0476406 (8p). VU0476406 is an important in vivo tool compound to enable translation of pharmacodynamics from rodent to NHP, and while data related to a Parkinson's disease model has been reported with 8p, this is the first disclosure of the optimization and discovery of VU0476406, as well as detailed pharmacology and DMPK properties...
June 1, 2017: Bioorganic & Medicinal Chemistry Letters
Mulias Lian, Mingjue Zhao, Caroline G Lee, Samuel S Chong
BACKGROUND: Preimplantation genetic diagnosis (PGD) of myotonic dystrophy type 1 (DM1) currently uses conventional PCR to detect nonexpanded dystrophia myotonica protein kinase (DMPK) alleles or triplet-primed PCR to detect the CTG-expanded alleles, coupled with analysis of linked microsatellite markers to increase diagnostic accuracy. We aimed to simplify the process of identification and selection of informative linked markers for application to DM1 PGD. METHODS: An in silico search was performed to identify all markers within 1-1...
June 2017: Clinical Chemistry
Aaron M Bender, Rebecca L Weiner, Vincent B Luscombe, Hyekyung P Cho, Colleen M Niswender, Darren W Engers, Thomas M Bridges, P Jeffrey Conn, Craig W Lindsley
This letter describes the synthesis and structure activity relationship (SAR) studies of structurally novel M4 antagonists, based on a 4,6-disubstituted core, identified from a high-throughput screening campaign. A multi-dimensional optimization effort enhanced potency at both human and rat M4 (IC50 s<300nM), with no substantial species differences noted. Moreover, CNS penetration proved attractive for this series (brain:plasma Kp,uu =0.87), while other DMPK attributes were addressed in the course of the optimization effort, providing low in vivo clearance in rat (CLp =5...
June 1, 2017: Bioorganic & Medicinal Chemistry Letters
Linda Fredlund, Susanne Winiwarter, Constanze Hilgendorf
In vitro permeability data have a central place in absorption risk assessments in drug discovery and development. For compounds where active efflux impacts permeability in vitro, the inherent passive membrane permeability ("intrinsic permeability") gives a concentration-independent measure of the compound's permeability. This work describes the validation of an in vitro intrinsic permeability assay and application of the data in a predictive in silico model. Apparent intrinsic permeability (Papp) across Caco-2 cell monolayers is determined in the presence of an optimized cocktail of chemical inhibitors toward the three major efflux transporters ABCB1, ABCC2, and ABCG2...
April 4, 2017: Molecular Pharmaceutics
Cecilie Rosting, Astrid Gjelstad, Trine Grønhaug Halvorsen
The combination of dried blood spots (DBS) and bottom-up LC-MS-based protein analysis was investigated in the present paper using six model proteins (1 mg/mL of each protein) with different physicochemical properties. Two different materials for DBS were examined: a water-soluble DBS material (carboxymethyl cellulose, (CMC)) and a commercially available (non-soluble) material (DMPK-C). The sample preparation was optimised regarding the water-soluble material and achieving acceptable repeatability of the signal was emphasised...
May 2017: Analytical and Bioanalytical Chemistry
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...
November 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
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