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சுருக்கம்

Developing Selective FPR2 Agonists can be a Potential Approach to Treat Moderate to Severe Asthma?

Senthil A Visaga, Harikesh Kalonia, Vinay Verma, Sandeep Sinha, Shashi Kant Singh, Swati Upadhyay, Sudhir Sahdev, Amita Pansari, Rajesh Kumar, Mahadev Bandgar, Narayan Karanjule, Raj Kumar Shirumalla, Kaoru Morishita, Ruchi Tandon*

Formyl Peptide Receptors (FPRs) play an important role in the modulation of inflammation. There has however been a lot of ambiguity in the past with regard to the pro and anti-inflammatory profiles of FPR family members. A few FPR2/FPR1 dual agonists are reported in the public domain for their anti-inflammatory properties along with associated toxicities. Targeting FPR1 alone on the other hand has been shown to result into both positive and negative outcomes. We, therefore, aimed to develop FPR2 agonists which were selective against FPR1 followed by evaluating their potential in mitigating the non-resolving inflammation in asthma. Extensive Structure-Activity-Relationship (SAR) studies were conducted on the imidazole and benzimidazole chemotypes and a few molecules were shortlisted based on their in vitro profile and Absorption, Distribution, Metabolism and Excretion (ADME) properties. Molecules with acceptable biological profile were then further evaluated in the mouse models of asthma. In this manuscript, we are reporting the identification of RCI compounds with low nanomolar potency for FPR2 agonism and >10,000 fold selectivity over FPR1 in Ca²⁺ release assay. Interestingly, selective FPR2 agonists also showed potency in the mouse models of asthma. Our studies hereby confirm that FPR2 agonism alone is sufficient to address asthma and FPR1 could be spared to avoid the ambiguity and undesirable side effects.