Identification of a novel orally bioavailable NLRP3 inflammasome inhibitor.
Sameer Agarwal, Jignesh P Pethani, Hardik A Shah, Vismit Vyas, Santosh Sasane, Harsh Bhavsar, Debdutta Bandyopadhyay, Poonam Giri, Kasinath Viswanathan, Mukul R Jain, Rajiv Sharma
Author Information
Sameer Agarwal: Zydus Research Centre, Cadila Healthcare Ltd., Sarkhej-Bavla N.H. No. 8 A, Moraiya, Ahmedabad 382 210, India. Electronic address: sameeragarwal@zyduscadila.com.
Jignesh P Pethani: Zydus Research Centre, Cadila Healthcare Ltd., Sarkhej-Bavla N.H. No. 8 A, Moraiya, Ahmedabad 382 210, India.
Hardik A Shah: Zydus Research Centre, Cadila Healthcare Ltd., Sarkhej-Bavla N.H. No. 8 A, Moraiya, Ahmedabad 382 210, India.
Vismit Vyas: Zydus Research Centre, Cadila Healthcare Ltd., Sarkhej-Bavla N.H. No. 8 A, Moraiya, Ahmedabad 382 210, India.
Santosh Sasane: Zydus Research Centre, Cadila Healthcare Ltd., Sarkhej-Bavla N.H. No. 8 A, Moraiya, Ahmedabad 382 210, India.
Harsh Bhavsar: Zydus Research Centre, Cadila Healthcare Ltd., Sarkhej-Bavla N.H. No. 8 A, Moraiya, Ahmedabad 382 210, India.
Debdutta Bandyopadhyay: Zydus Research Centre, Cadila Healthcare Ltd., Sarkhej-Bavla N.H. No. 8 A, Moraiya, Ahmedabad 382 210, India.
Poonam Giri: Zydus Research Centre, Cadila Healthcare Ltd., Sarkhej-Bavla N.H. No. 8 A, Moraiya, Ahmedabad 382 210, India.
Kasinath Viswanathan: Zydus Research Centre, Cadila Healthcare Ltd., Sarkhej-Bavla N.H. No. 8 A, Moraiya, Ahmedabad 382 210, India.
Mukul R Jain: Zydus Research Centre, Cadila Healthcare Ltd., Sarkhej-Bavla N.H. No. 8 A, Moraiya, Ahmedabad 382 210, India.
Rajiv Sharma: Zydus Research Centre, Cadila Healthcare Ltd., Sarkhej-Bavla N.H. No. 8 A, Moraiya, Ahmedabad 382 210, India. Electronic address: Rajiv.Sharma@zyduscadila.com.
NLRP3 inflammasome mediated release of interleukin-1β (IL-1β) has been implicated in various diseases, including COVID-19. In this study, rationally designed alkenyl sulfonylurea derivatives were identified as novel, potent and orally bioavailable NLRP3 inhibitors. Compound 7 was found to be potent (IL-1β IC = 35 nM; IL-18 IC = 33 nM) and selective NLRP3 inflammasome inhibitor with excellent pharmacokinetic profile having oral bioavailability of 99% in mice.
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Administration, Oral
Animals
Betacoronavirus
COVID-19
Cell Line, Tumor
Coronavirus Infections
Cytochrome P-450 CYP2C8 Inhibitors
Cytochrome P-450 CYP2C9 Inhibitors
Dogs
Drug Stability
Humans
Inflammasomes
Interleukin-1beta
Mice, Inbred C57BL
Microsomes, Liver
Molecular Structure
NLR Family, Pyrin Domain-Containing 3 Protein
Pandemics
Pneumonia, Viral
Rats
SARS-CoV-2
Structure-Activity Relationship
Sulfonylurea Compounds
Cytochrome P-450 CYP2C8 Inhibitors
Cytochrome P-450 CYP2C9 Inhibitors
IL1B protein, human
Inflammasomes
Interleukin-1beta
NLR Family, Pyrin Domain-Containing 3 Protein
NLRP3 protein, human
Nlrp3 protein, mouse
Sulfonylurea Compounds
