A5054309916- Computational Drug Discovery Methods
- X-ray Diffraction in Crystallography
- Crystallization and Solubility Studies
- Chemical Synthesis and Analysis
- Synthesis and Catalytic Reactions
- Catalytic C–H Functionalization Methods
- Click Chemistry and Applications
- Neuroscience and Neuropharmacology Research
- Fluorine in Organic Chemistry
- Pharmacogenetics and Drug Metabolism
- Asymmetric Synthesis and Catalysis
- Chemical Reaction Mechanisms
- Sulfur-Based Synthesis Techniques
- Alzheimer's disease research and treatments
- Protein Degradation and Inhibitors
- Asymmetric Hydrogenation and Catalysis
- Axial and Atropisomeric Chirality Synthesis
- Chemical Reactions and Isotopes
- Phosphodiesterase function and regulation
- Cholinesterase and Neurodegenerative Diseases
- Radical Photochemical Reactions
- Receptor Mechanisms and Signaling
- Machine Learning in Materials Science
- Synthesis and biological activity
- Synthetic Organic Chemistry Methods
Pfizer (United States)
2011-2024
Roche (Switzerland)
2021-2024
Center for Pain and the Brain
2016
Scripps Research Institute
2007-2013
Urbana University
2012
University of Illinois Urbana-Champaign
2012
University of Washington
2011
University of California, San Diego
2007-2008
University of Cambridge
2003-2006
Wild-type LRRK2 is activated in nigrostriatal dopamine neurons idiopathic Parkinson’s disease and plays a pathogenic role this neurodegenerative disorder.
Modern drug discovery is contingent on identifying lead compounds and rapidly synthesizing analogues. The use of a common pharmacophore to direct multiple divergent C–H functionalizations particularly attractive approach. Herein, we demonstrate the viability late-stage diversification through functionalization sulfonamides, an important class pharmacophores found in nearly 200 drugs currently market, including non-steroidal anti-inflammatory blockbuster celecoxib. We developed set six...
Replacement of the central, para-substituted fluorophenyl ring in γ-secretase inhibitor 1 (BMS-708,163) withthe bicyclo[1.1.1]pentane motif led to discovery compound 3, an equipotent enzyme with significant improvements passive permeability and aqueous solubility. The modified biopharmaceutical properties 3 translated into excellent oral absorption characteristics (∼4-fold ↑ Cmax AUC values relative 1) a mouse model inhibition. In addition, SAR studies other replacements indicate intrinsic...
A combination of weakly coordinating auxiliaries and ligand acceleration allows for the development both ortho- meta-selective C–H olefination phenol derivatives. These reactions demonstrate feasibility directing functionalizations when functional groups are distal to target bonds. The meta-C–H functionalization electron-rich derivatives is unprecedented orthogonal previous electrophilic substitution phenols in terms regioselectivity. methods also applied functionalize α-phenoxyacetic acids,...
A wide range of halogenated bicyclo[1.1.1]pentanes are accessed by functional group tolerant radical ring-opening tricyclo[1.1.1.0<sup>1,3</sup>]pentane, using triethylborane as initiator.
A convenient synthesis of imatinib, a potent inhibitor ABL1 kinase and widely prescribed drug for the treatment variety leukemias, was devised applied to construction series novel imatinib analogues featuring number non-aromatic structural motifs in place parent molecule's phenyl moiety. These were subsequently evaluated their biopharmaceutical properties (e.g., inhibitory activity, cytotoxicity). The bicyclo[1.1.1]pentane- cubane-containing found possess higher themodynamic solubility,...
Morphological changes in the lungs of macaques induced by several different LRRK2 inhibitors are reversible and do not lead to lung deficits.
Abstract Late-stage functionalization is an economical approach to optimize the properties of drug candidates. However, chemical complexity molecules often makes late-stage diversification challenging. To address this problem, a platform based on geometric deep learning and high-throughput reaction screening was developed. Considering borylation as critical step in functionalization, computational model predicted yields for diverse conditions with mean absolute error margin 4–5%, while...
The molecular design, chemical synthesis, and biological evaluation of two distinct series platensimycin analogues with varying degrees complexity are described. first compounds probes the importance benzoic acid subunit molecule, while second explores tetracyclic cage domain. data obtained reveal that, substituted domain is a highly conserved structural motif within active strict functional group requirements, molecule can tolerate considerable modifications without losing action. These...
Preclinical drug metabolism studies play a key role in the lead identification and optimization process discovery. Characterization of metabolic pathways new chemical entities is an integral part discovery not only optimizing clearance properties but also eliminating potential safety concerns associated with formation protein and/or DNA-reactive metabolites. Metabolism early have been used to identify soft spots leading high instability, characterization active Availability such information...
A metabolism-based approach toward the optimization of a series N-arylsulfonamide-based γ-secretase inhibitors is reported. The lead cyclohexyl analogue 6 suffered from extensive oxidation on cycloalkyl motif by cytochrome P450 3A4, translating into poor human liver microsomal stability. Knowledge metabolic pathways triggered structure-activity relationship study aimed at lowering lipophilicity through introduction polarity. This effort led to several tetrahydropyran and tetrahydrofuran...
We have observed previously that modification of ring size and substitution pattern may be used as a strategy to mitigate the metabolic instability cycloalkyl ethers. In this article, we introduce medicinal chemistry design parameter named "lipophilic metabolism efficiency" (LipMetE) indicates these changes in stability can largely ascribed lipophilicity. Our matched molecular pair analysis also finding is general phenomenon, widely across different chemotypes. It our hope both LipMetE...
The chemical synthesis and biological evaluation of carbaplatensimycin, the carbon analogue recently reported antibiotic platensimycin has been accomplished. Carbaplatensimycin exhibited similar potency to natural product as an antibacterial agent against a variety strains, including methicilin- vancomycin-resistant bacteria.
Tandem reaction sequences that selectively convert multiple C–H bonds of abundant hydrocarbon feedstocks to functionalized materials enable rapid buildup molecular complexity in an economical way. A tandem amination/vinylic arylation sequence is described under Pd(II)/sulfoxide-catalysis furnishes a wide range α- and β-homophenylalanine precursors from commodity α-olefins readily available aryl boronic acids. General routes enantiopure amino acid esters densely homophenylalanine derivatives...
Palladium-containing perovskites (LaFe0.57Co0.38Pd0.05O3) have been exploited as recoverable and reuseable catalysts in Suzuki coupling reactions; residual levels of Pd after removal the catalyst by filtration are low (2 ppm) despite evidence that reaction is occurring via a homogeneous process.
We report novel polymyxin analogues with improved antibacterial in vitro potency against resistant recent clinical isolates of Acinetobacter baumannii and Pseudomonas aeruginosa . In addition, a human renal cell assay (hRPTEC) was used to inform structure-toxicity relationships further differentiate analogues. Replacement the Dab-3 residue Dap-3 combination relatively polar 6-oxo-1-phenyl-1,6-dihydropyridine-3-carbonyl side chain as fatty acyl replacement yielded analogue 5x, which...
A novel series of pyrazolopyrazines is herein disclosed as mGluR5 negative allosteric modulators (NAMs). Starting from a high-throughput screen (HTS) hit (1), systematic structure-activity relationship (SAR) study was conducted with specific focus on balancing pharmacological potency physicochemical and pharmacokinetic (PK) properties. This effort led to the discovery 1-methyl-3-(4-methylpyridin-3-yl)-6-(pyridin-2-ylmethoxy)-1H-pyrazolo[3,4-b]pyrazine (PF470, 14) highly potent, selective,...
Late-stage oxidation using liver microsomes was applied to phosphodiesterase 2 inhibitor 1 reduce its clearance by cytochrome P450 enzymes, introduce renal clearance, and minimize the risk for victim drug-drug interactions. This approach yielded PF-06815189 (2) with improved physicochemical properties a mixed metabolic profile. example highlights importance of C-H diversification methods drug discovery.
Herein we describe the design and synthesis of a series pyridopyrazine-1,6-dione γ-secretase modulators (GSMs) for Alzheimer's disease (AD) that achieve good alignment potency, metabolic stability, low MDR efflux ratios, while also maintaining favorable physicochemical properties. Specifically, incorporation fluorine enabled metabolically less liable lipophilic alkyl substituents to increase potency without compromising sp(3)-character. The lead compound 21 (PF-06442609) displayed rodent...
In this report, we describe a method whereby lead molecules can be converted into several new analogues each using liver microsomes. Less than one micromole of substrate is incubated with microsomes (mouse, rat, hamster, guinea pig, rabbit, dog, monkey, or human) to produce multiple products which are isolated and analyzed by quantitative cryomicroprobe NMR (qNMR) spectroscopy. The solutions from qNMR analysis were then used as stocks that diluted biochemical assays. Nine human...
The origin of small-molecule leads that were pursued across the independent research organizations Roche and Genentech from 2009 to 2020 is described. identified chemical series are derived a variety lead-finding methods, which include public information, high-throughput screening (both full file focused), fragment-based design, DNA-encoded library technology, use legacy internal data, in-licensing, de novo design (often structure-based). translation lead into in vivo tool compounds...