Search

Your search keyword '"Clark, Charles G."' showing total 4 results
Start Over Author "Clark, Charles G." Journal bioorganic medicinal chemistry letters
4 results on '"Clark, Charles G."'

1. Structure based design of macrocyclic factor XIa inhibitors: Discovery of cyclic P1 linker moieties with improved oral bioavailability.

Author

Clark CG, Rossi KA, Corte JR, Fang T, Smallheer JM, De Lucca I, Nirschl DS, Orwat MJ, Pinto DJP, Hu Z, Wang Y, Yang W, Jeon Y, Ewing WR, Myers JE Jr, Sheriff S, Lou Z, Bozarth JM, Wu Y, Rendina A, Harper T, Zheng J, Xin B, Xiang Q, Luettgen JM, Seiffert DA, Wexler RR, and Lam PYS

Subjects
Administration, Oral, Biological Availability, Humans, Ligands, Macrocyclic Compounds pharmacology, Models, Molecular, Molecular Structure, Serine Proteinase Inhibitors pharmacology, Structure-Activity Relationship, Drug Design, Drug Discovery, Factor XIa antagonists & inhibitors, Macrocyclic Compounds administration & dosage, Macrocyclic Compounds chemistry, Serine Proteinase Inhibitors administration & dosage, Serine Proteinase Inhibitors chemistry
Abstract

This manuscript describes the discovery of a series of macrocyclic inhibitors of FXIa with oral bioavailability. Assisted by structure based drug design and ligand bound X-ray crystal structures, the group linking the P1 moiety to the macrocyclic core was modified with the goal of reducing H-bond donors to improve pharmacokinetic performance versus 9. This effort resulted in the discovery of several cyclic P1 linkers, exemplified by 10, that are constrained mimics of the bioactive conformation displayed by the acrylamide linker of 9. These cyclic P1 linkers demonstrated enhanced bioavailability and improved potency., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Published
2019
Full Text
View/download PDF

2. Identification of 1-{2-[4-chloro-1'-(2,2-dimethylpropyl)-7-hydroxy-1,2-dihydrospiro[indole-3,4'-piperidine]-1-yl]phenyl}-3-{5-chloro-[1,3]thiazolo[5,4-b]pyridin-2-yl}urea, a potent, efficacious and orally bioavailable P2Y(1) antagonist as an antiplatelet agent.

Author

Jeon YT, Yang W, Qiao JX, Li L, Ruel R, Thibeault C, Hiebert S, Wang TC, Wang Y, Liu Y, Clark CG, Wong HS, Zhu J, Wu DR, Sun D, Chen BC, Mathur A, Chacko SA, Malley M, Chen XQ, Shen H, Huang CS, Schumacher WA, Bostwick JS, Stewart AB, Price LA, Hua J, Li D, Levesque PC, Seiffert DA, Rehfuss R, Wexler RR, and Lam PY

Subjects
Administration, Oral, Animals, Dogs, Half-Life, Macaca fascicularis, Phenylurea Compounds pharmacokinetics, Phenylurea Compounds pharmacology, Phenylurea Compounds therapeutic use, Platelet Aggregation drug effects, Platelet Aggregation Inhibitors pharmacokinetics, Platelet Aggregation Inhibitors pharmacology, Platelet Aggregation Inhibitors therapeutic use, Purinergic P2Y Receptor Antagonists pharmacokinetics, Purinergic P2Y Receptor Antagonists pharmacology, Purinergic P2Y Receptor Antagonists therapeutic use, Rats, Receptors, Purinergic P2Y1 metabolism, Structure-Activity Relationship, Thiazoles pharmacokinetics, Thiazoles pharmacology, Thiazoles therapeutic use, Thrombosis drug therapy, Urea pharmacokinetics, Urea pharmacology, Urea therapeutic use, Phenylurea Compounds chemistry, Platelet Aggregation Inhibitors chemistry, Purinergic P2Y Receptor Antagonists chemistry, Receptors, Purinergic P2Y1 chemistry, Thiazoles chemistry, Urea analogs & derivatives
Abstract

Spiropiperidine indoline-substituted diaryl ureas had been identified as antagonists of the P2Y1 receptor. Enhancements in potency were realized through the introduction of a 7-hydroxyl substitution on the spiropiperidinylindoline chemotype. SAR studies were conducted to improve PK and potency, resulting in the identification of compound 3e, a potent, orally bioavailable P2Y1 antagonist with a suitable PK profile in preclinical species. Compound 3e demonstrated a robust antithrombotic effect in vivo and improved bleeding risk profile compared to the P2Y12 antagonist clopidogrel in rat efficacy/bleeding models., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Published
2014
Full Text
View/download PDF

3. Discovery of diarylurea P2Y(1) antagonists with improved aqueous solubility.

Author

Wang TC, Qiao JX, Clark CG, Jua J, Price LA, Wu Q, Chang M, Zheng J, Huang CS, Everlof G, Schumacher WA, Wong PC, Seiffert DA, Stewart AB, Bostwick JS, Crain EJ, Watson CA, Rehfuss R, Wexler RR, and Lam PY

Subjects
Animals, Caco-2 Cells, Disease Models, Animal, Drug Evaluation, Preclinical, Fibrinolytic Agents chemical synthesis, Fibrinolytic Agents pharmacokinetics, Half-Life, Humans, Microsomes, Liver metabolism, Partial Thromboplastin Time, Phenylurea Compounds pharmacokinetics, Phenylurea Compounds therapeutic use, Platelet Aggregation drug effects, Purinergic P2Y Receptor Antagonists pharmacokinetics, Purinergic P2Y Receptor Antagonists therapeutic use, Pyridines pharmacokinetics, Pyridines therapeutic use, Rabbits, Rats, Receptors, Purinergic P2Y1 metabolism, Solubility, Structure-Activity Relationship, Thrombosis drug therapy, Urea pharmacokinetics, Urea therapeutic use, Water chemistry, Fibrinolytic Agents chemistry, Phenylurea Compounds chemistry, Purinergic P2Y Receptor Antagonists chemistry, Pyridines chemistry, Receptors, Purinergic P2Y1 chemistry, Urea chemistry
Abstract

Preclinical data suggests that P2Y1 antagonists, such as diarylurea compound 1, may provide antithrombotic efficacy similar to P2Y12 antagonists and may have the potential of providing reduced bleeding liabilities. This manuscript describes a series of diarylureas bearing solublizing amine side chains as potent P2Y1 antagonists. Among them, compounds 2l and 3h had improved aqueous solubility and maintained antiplatelet activity compared with compound 1. Compound 2l was moderately efficacious in both rat and rabbit thrombosis models and had a moderate prolongation of bleeding time in rats similar to that of compound 1., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Published
2013
Full Text
View/download PDF

4. Discovery of 3-amino-4-chlorophenyl P1 as a novel and potent benzamidine mimic via solid-phase synthesis of an isoxazoline library.

Author

Lam PY, Adams JJ, Clark CG, Calhoun WJ, Luettgen JM, Knabb RM, and Wexler RR

Subjects
Animals, Benzamidines chemistry, Enzyme Inhibitors chemical synthesis, Humans, Isoxazoles pharmacology, Molecular Mimicry, Structure-Activity Relationship, Combinatorial Chemistry Techniques, Factor Xa Inhibitors, Isoxazoles chemical synthesis
Abstract

In an effort to identify orally bioavailable factor Xa inhibitors, two isoxazolines libraries were prepared to scan for novel P1 ligands. From this work, 4-chloro-3-aniline was identified as a novel and potent benzamidine mimic.

Published
2003
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results