Dataset Information

Discovery and Optimization of a Novel Series of Competitive and Central Nervous System-Penetrant Protease-Activated Receptor 4 (PAR4) Inhibitors.

ABSTRACT: The detailed pharmacology and therapeutic potential of the central PAR4 receptors are poorly understood due to a lack of potent, selective, and brain-penetrant tool compounds. Despite this, robust data with biochemical and genetic tools show the therapeutic potential of PAR4 antagonists in traumatic brain injury, Alzheimer's disease, Parkinson's disease, and other neurodegenerative disorders with a neuroinflammatory component. Thus, we performed a functional HTS campaign, identified a fundamentally new PAR4 competitive inhibitor chemotype, optimized this new series (increased potency >45-fold), discovered enantiospecific activity (though opposing preference for human versus mouse PAR4), and engendered high central nervous system penetration (rat K_p's of 0.52 to 4.2 and K_p,uu's of 0.52 to 1.2).

SUBMITTER: Bertron JL

PROVIDER: S-EPMC8823334 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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Publications

Discovery and Optimization of a Novel Series of Competitive and Central Nervous System-Penetrant Protease-Activated Receptor 4 (PAR4) Inhibitors.

Bertron Jeanette L JL Duvernay Matthew T MT Mitchell Sidnee G SG Smith Shannon T ST Maeng Jae G JG Blobaum Anna L AL Davis Dexter C DC Meiler Jens J Hamm Heidi E HE Lindsley Craig W CW

ACS chemical neuroscience 20211202 24

The detailed pharmacology and therapeutic potential of the central PAR4 receptors are poorly understood due to a lack of potent, selective, and brain-penetrant tool compounds. Despite this, robust data with biochemical and genetic tools show the therapeutic potential of PAR4 antagonists in traumatic brain injury, Alzheimer's disease, Parkinson's disease, and other neurodegenerative disorders with a neuroinflammatory component. Thus, we performed a functional HTS campaign, identified a fundamenta ...[more]

PMID: 34855359

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Project description:The central nervous system (CNS) is the major area that is affected by aging. Alzheimer's disease (AD), Parkinson's disease (PD), brain cancer, and stroke are the CNS diseases that will cost trillions of dollars for their treatment. Achievement of appropriate blood-brain barrier (BBB) penetration is often considered a significant hurdle in the CNS drug discovery process. On the other hand, BBB penetration may be a liability for many of the non-CNS drug targets, and a clear understanding of the physicochemical and structural differences between CNS and non-CNS drugs may assist both research areas. Because of the numerous and challenging issues in CNS drug discovery and the low success rates, pharmaceutical companies are beginning to deprioritize their drug discovery efforts in the CNS arena. Prompted by these challenges and to aid in the design of high-quality, efficacious CNS compounds, we analyzed the physicochemical property and the chemical structural profiles of 317 CNS and 626 non-CNS oral drugs. The conclusions derived provide an ideal property profile for lead selection and the property modification strategy during the lead optimization process. A list of substructural units that may be useful for CNS drug design was also provided here. A classification tree was also developed to differentiate between CNS drugs and non-CNS oral drugs. The combined analysis provided the following guidelines for designing high-quality CNS drugs: (i) topological molecular polar surface area of <76 Å(2) (25-60 Å(2)), (ii) at least one (one or two, including one aliphatic amine) nitrogen, (iii) fewer than seven (two to four) linear chains outside of rings, (iv) fewer than three (zero or one) polar hydrogen atoms, (v) volume of 740-970 Å(3), (vi) solvent accessible surface area of 460-580 Å(2), and (vii) positive QikProp parameter CNS. The ranges within parentheses may be used during lead optimization. One violation to this proposed profile may be acceptable. The chemoinformatics approaches for graphically analyzing multiple properties efficiently are presented.

Dataset Information

Discovery and Optimization of a Novel Series of Competitive and Central Nervous System-Penetrant Protease-Activated Receptor 4 (PAR4) Inhibitors.

Publications

Discovery and Optimization of a Novel Series of Competitive and Central Nervous System-Penetrant Protease-Activated Receptor 4 (PAR4) Inhibitors.

Similar Datasets

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