5198-86-7Relevant academic research and scientific papers
Synthesis and evaluation of novel and potent protease activated receptor 4 (PAR4) antagonists based on a quinazolin-4(3H)-one scaffold
Kong, Yi,Li, Shanshan,Liu, Shangde,Xie, Roujie,Yuan, Duo,Zhu, Xiong
supporting information, (2021/08/16)
Protease activated receptor 4 (PAR4) is an important target in antiplatelet therapy to reduce the risk of heart attack and thrombotic complications in stroke. PAR4 antagonists can prevent harmful and stable thrombus growth, while retaining initial thrombus formation, by acting on the late diffusion stage of platelet aggregation, and may provide a safer alternative to other antiplatelet agents. To date, only two PAR4 antagonists, BMS-986120 and BMS-986141 have entered clinical trials for thrombosis. Thus, the development of a potent and selective PAR4 antagonist with a novel chemotype is highly desirable. In this study, we explored the activity of quinazolin-4(3H)-one-based PAR4 antagonists, beginning with their IDT analogues. By repeated structural optimisation, we developed a series of highly selective PAR4 antagonists with nanomolar potency on human platelets. Of these, 13 and 30g, with an 8-benzo[d]thiazol-2-yl-substituted quinazolin-4(3H)-one structure, showed optimal activity (h. PAR4-AP PRP IC50 = 19.6 nM and 6.59 nM, respectively) on human platelets. Furthermore, 13 and 30g showed excellent selectivity for PAR4 versus PAR1 and other receptors (IC50s > 10 μM) on human platelets. And 13 and 30g were lack of cross-reactivity for PAR1 or PAR2 (PAR1 AP FLIPR IC50 > 3162 nM, PAR2 AP FLIPR IC50 > 1000 nM) in the calcium mobilization assays. Metabolic stability assays and cytotoxicity tests of 13 and 30g indicated that these compounds could sever as promising drug candidates for the development of novel PAR4 antagonists. In summary, the quinazolin-4(3H)-one-based analogues are the first reported chemotypes with excellent activity and selectivity against PAR4, and, in the current study, we expanded the structural diversity of PAR4 antagonists. The two compounds, 13 and 30g, found in our study could be promising starting points with great potential for further research in antiplatelet therapy.
NLRP MODULATORS
-
Page/Page column 346; 347, (2020/01/31)
In one aspect, compounds of Formula AA, or a pharmaceutically acceptable salt thereof, are featured: or a pharmaceutically acceptable salt thereof, wherein the variables shown in Formula A can be as defined anywhere herein.
NLRP MODULATORS
-
Page/Page column 346-347, (2020/01/31)
In one aspect, compounds of Formula AA, or a pharmaceutically acceptable salt thereof, are featured: or a pharmaceutically acceptable salt thereof, wherein the variables shown in Formula A can be as defined anywhere herein, useful to treat connected to the modulation of NRLP3.
SULFONIMIDAMIDE COMPOUNDS AND COMPOSITIONS FOR TREATING CONDITIONS ASSOCIATED WITH NLRP ACTIVITY
-
Page/Page column 454-455, (2020/08/13)
In one aspect, compounds of Formula AA, or a pharmaceutically acceptable salt thereof, are featured: (Formula AA) or a pharmaceutically acceptable salt thereof, wherein the variables shown in Formula A can be as defined anywhere herein.
METHODS OF TREATING CANCER
-
Paragraph 00204, (2020/06/10)
The present disclosure relates to methods of treating cancer in a patient using a combination of an inhibitor of an immune checkpoint protein and an indole compound or its phosphate derivative.
COMPOUNDS AND COMPOSITIONS FOR TREATING CONDITIONS ASSOCIATED WITH NLRP ACTIVITY
-
Page/Page column 445, (2019/02/13)
In one aspect, compounds of Formula AA, or a pharmaceutically acceptable salt thereof, are featured.The variables shown in Formula AA are as defined in the claims. The compounds of formula AA are NLRP3 activity modulators and, as such, can be used in the treatment of metabolic disorders (e.g. Type 2 diabetes, atherosclerosis, obesity or gout), a disease of the central nervous system (e.g. Alzheimer's disease, multiple sclerosis, Amyotrophic Lateral Sclerosis or Parkinson's disease), lung disease (e.g. asthma, COPD or pulmonary idiopathic fibrosis), liver disease (e.g. NASH syndrome, viral hepatitis or cirrhosis), pancreatic disease (e.g. acute pancreatitis or chronic pancreatitis), kidney disease (e.g. acute kidney injury or chronic kidney injury), intestinal disease (e.g. Crohn's disease or Ulcerative Colitis), skin disease (e.g. psoriasis), musculoskeletal disease (e.g. scleroderma), a vessel disorder (e.g. giant cell arteritis), a disorder of the bones (e.g. osteoarthritis, osteoporosis or osteopetrosis disorders), eye disease (e.g. glaucoma or macular degeneration), a disease caused by viral infection (e.g. HIV or AIDS), an autoimmune disease (e.g. Rheumatoid Arthritis, Systemic Lupus Erythematosus or Autoimmune Thyroiditis), cancer or aging.
COMPOUNDS AND COMPOSITIONS FOR TREATING CONDITIONS ASSOCIATED WITH NLRP ACTIVITY
-
Page/Page column 393, (2019/02/13)
In one aspect, compounds of Formula AA, or a pharmaceutically acceptable salt thereof, are featured. The variables shown in Formula AA are as defined in the claims. The compounds of formula AA are NLRP3 activity modulators and, as such, can be used in the treatment of metabolic disorders (e.g. Type 2 diabetes, atherosclerosis, obesity or gout), a disease of the central nervous system (e.g. Alzheimer's disease, multiple sclerosis, Amyotrophic Lateral Sclerosis or Parkinson's disease), lung disease (e.g. asthma, COPD or pulmonary idiopathic fibrosis), liver disease (e.g. NASH syndrome, viral hepatitis or cirrhosis), pancreatic disease (e.g. acute pancreatitis or chronic pancreatitis), kidney disease (e.g. acute kidney injury or chronic kidney injury), intestinal disease (e.g. Crohn's disease or Ulcerative Colitis), skin disease (e.g. psoriasis), musculoskeletal disease (e.g. scleroderma), a vessel disorder (e.g. giant cell arteritis), a disorder of the bones (e.g. osteoarthritis, osteoporosis or osteopetrosis disorders), eye disease (e.g. glaucoma or macular degeneration), a disease caused by viral infection (e.g. HIV or AIDS), an autoimmune disease (e.g. Rheumatoid Arthritis, Systemic Lupus Erythematosus or Autoimmune Thyroiditis), cancer or aging.
DYNAMIN-1-LIKE PROTEIN INHIBITORS
-
Page/Page column 72, (2018/11/22)
This application is directed to inhibitors of dynamin-l-like protein (Drpl) represented by the following structural formula (I): and methods for their use, such as to treat one or more DRPl-related diseases.
Oxazolidinone compounds and its use in medicine
-
Paragraph 0281; 0283; 0284, (2017/08/10)
The invention relates to an oxazolidinone compound and an application thereof to preparation of drugs for preventing and treating thromboembolic diseases and in particular relates to a compound shown in a general formula (I) in the specification or stereoisomers, geometrical isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites and pharmaceutically acceptable salts or prodrugs of the compound. All the variables are defined in the specification. The invention also relates to an application of the compound shown in the general formula (I) or the stereoisomers, geometrical isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites and pharmaceutically acceptable salts or prodrugs of the compound as drugs and in particular relates to an application of the substances as drugs for preventing and treating thromboembolic diseases.
Oxazolidinone compounds and its use in medicine
-
Paragraph 0142; 0143; 0144; 0145, (2017/08/25)
The invention relates to an oxazolidinone compound and an application thereof to preparation of drugs for preventing and treating thromboembolic diseases and in particular relates to a compound shown in a general formula (I) in the specification or stereoisomers, geometrical isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites and pharmaceutically acceptable salts or prodrugs of the compound. All the variables are defined in the specification. The invention also relates to an application of the compound shown in the general formula (I) or the stereoisomers, geometrical isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites and pharmaceutically acceptable salts or prodrugs of the compound as drugs and in particular relates to an application of the substances as drugs for preventing and treating thromboembolic diseases.
