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

doi:10.1016/j.bmcl.2020.127571

Identification of a novel orally bioavailable NLRP3 inflammasome inhibitor

Bioorg Med Chem Lett. 2020 Nov 1;30(21):127571. doi: 10.1016/j.bmcl.2020.127571. Epub 2020 Sep 24.

Affiliations

¹ Zydus Research Centre, Cadila Healthcare Ltd., Sarkhej-Bavla N.H. No. 8 A, Moraiya, Ahmedabad 382 210, India. Electronic address: sameeragarwal@zyduscadila.com.
² Zydus Research Centre, Cadila Healthcare Ltd., Sarkhej-Bavla N.H. No. 8 A, Moraiya, Ahmedabad 382 210, India.
³ Zydus Research Centre, Cadila Healthcare Ltd., Sarkhej-Bavla N.H. No. 8 A, Moraiya, Ahmedabad 382 210, India. Electronic address: Rajiv.Sharma@zyduscadila.com.

Abstract

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 IC₅₀ = 35 nM; IL-18 IC₅₀ = 33 nM) and selective NLRP3 inflammasome inhibitor with excellent pharmacokinetic profile having oral bioavailability of 99% in mice.

Keywords: Acute respiratory distress syndrome (ARDS); Coronavirus disease 2019 (COVID-19); Inflammation; Interleukin-1β (IL-1β); NLRP3; NLRP3 inflammasome; Sulfonylurea.

MeSH terms

Administration, Oral
Animals
Betacoronavirus
COVID-19
Cell Line, Tumor
Coronavirus Infections
Cytochrome P-450 CYP2C8 Inhibitors / administration & dosage
Cytochrome P-450 CYP2C8 Inhibitors / chemical synthesis
Cytochrome P-450 CYP2C8 Inhibitors / pharmacokinetics
Cytochrome P-450 CYP2C8 Inhibitors / pharmacology
Cytochrome P-450 CYP2C9 Inhibitors / administration & dosage
Cytochrome P-450 CYP2C9 Inhibitors / chemical synthesis
Cytochrome P-450 CYP2C9 Inhibitors / pharmacokinetics
Cytochrome P-450 CYP2C9 Inhibitors / pharmacology
Dogs
Drug Stability
Humans
Inflammasomes / antagonists & inhibitors*
Interleukin-1beta / antagonists & inhibitors
Mice, Inbred C57BL
Microsomes, Liver / metabolism
Molecular Structure
NLR Family, Pyrin Domain-Containing 3 Protein / antagonists & inhibitors*
Pandemics
Pneumonia, Viral
Rats
SARS-CoV-2
Structure-Activity Relationship
Sulfonylurea Compounds / administration & dosage
Sulfonylurea Compounds / chemical synthesis
Sulfonylurea Compounds / pharmacokinetics
Sulfonylurea Compounds / pharmacology*

Substances

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