TY - JOUR
T1 - The formyl peptide receptors FPR1 and FPR2 as targets for inflammatory disorders
T2 - recent advances in the development of small-molecule agonists
AU - Yi, Xiangyan
AU - Tran, Eric
AU - Odiba, Jephthah O.
AU - Qin, Cheng Xue
AU - Ritchie, Rebecca H.
AU - Baell, Jonathan B.
N1 - Funding Information:
In subsequent work, the enantiomeric preferences of the pyridazinone anilide chemotype at C-4 (methoxybenzyl side) and C-2 (acetamide side chain) were reported against both FPR1 and FPR2 (Fig. 5) [111,112]. Regarding FPR1, the chirality at C-4 of the unsaturated pyridazine ring (16) was found to be only a marginal factor in influencing activity, with a respective (S)-16 EC50 value of 20 μM and (R)-16 EC50 value of 24 μM. This was also the case for FPR2, against which both (S)-enantiomers (EC50 = 11 μM) and (R)-enantiomers (EC50 = 10 μM) were also slightly more potent compared with FPR1 [111]. The absolute configuration of the enantiomers of 16 above was established by X-ray crystallographic analysis and supported by polarimetric analysis, and comparative elution sequence during chiral HPLC-UV analysis [111].This research was supported by the National Health and Medical Research Council of Australia (NHMRC), including the NHMRC Independent Research Institutes Infrastructure Support Scheme (IRIISS grant no. 361646), NHMRC project grants APP1025581 and APP1079351, APP1120853, to JBB and RHR) and Development Grant (APP1155527, to JBB, CXQ and RHR). The NHMRC also provided Fellowship support for JBB (2018–2019 Senior Research Fellowship APP1025581; 2017-Principal Research Fellowship APP1117602) and RHR (Senior Research Fellowship APP1059960). CXQ is a Future Leader fellow (ID: #102787). The authors acknowledge the Australian Federal Government Education Investment Fund Super Science Initiative and the Victorian State Government (OIS grant), Victoria Science Agenda Investment Fund for infrastructure support. The authors acknowledge the facilities, and the scientific and technical assistance of the Australian Translational Medicinal Chemistry Facility (ATMCF), Monash Institute of Pharmaceutical Sciences (MIPS). ATMCF is supported by Therapeutic Innovation Australia (TIA). TIA is supported by the Australian Government through the National Collaborative Research Infrastructure Strategy (NCRIS) program. We are thankful to these organisations for this support.
Funding Information:
This research was supported by the National Health and Medical Research Council of Australia (NHMRC) , including the NHMRC Independent Research Institutes Infrastructure Support Scheme (IRIISS grant no. 361646 ), NHMRC project grants APP1025581 and APP1079351 , APP1120853 , to JBB and RHR) and Development Grant ( APP1155527 , to JBB, CXQ and RHR). The NHMRC also provided Fellowship support for JBB (2018–2019 Senior Research Fellowship APP1025581 ; 2017-Principal Research Fellowship APP1117602 ) and RHR (Senior Research Fellowship APP1059960 ). CXQ is a Future Leader fellow (ID: # 102787 ). The authors acknowledge the Australian Federal Government Education Investment Fund Super Science Initiative and the Victorian State Government (OIS grant), Victoria Science Agenda Investment Fund for infrastructure support. The authors acknowledge the facilities, and the scientific and technical assistance of the Australian Translational Medicinal Chemistry Facility (ATMCF), Monash Institute of Pharmaceutical Sciences (MIPS). ATMCF is supported by Therapeutic Innovation Australia (TIA). TIA is supported by the Australian Government through the National Collaborative Research Infrastructure Strategy (NCRIS) program . We are thankful to these organisations for this support.
Publisher Copyright:
© 2023 The Authors
PY - 2024/2/5
Y1 - 2024/2/5
N2 - Formyl peptide receptors (FPRs) comprise a class of chemoattractant pattern recognition receptors, for which several physiological functions like host-defences, as well as the regulation of inflammatory responses, have been ascribed. With accumulating evidence that agonism of FPR1/FPR2 can confer pro-resolution of inflammation, increased attention from academia and industry has led to the discovery of new and interesting small-molecule FPR1/FPR2 agonists. Focused attention on the development of appropriate physicochemical and pharmacokinetic profiles is yielding synthesis of new compounds with promising in vivo readouts. This review presents an overview of small-molecule FPR1/FPR2 agonist medicinal chemistry developed over the past 20 years, with a particular emphasis on interrogation in the increasingly sophisticated bioassays which have been developed.
AB - Formyl peptide receptors (FPRs) comprise a class of chemoattractant pattern recognition receptors, for which several physiological functions like host-defences, as well as the regulation of inflammatory responses, have been ascribed. With accumulating evidence that agonism of FPR1/FPR2 can confer pro-resolution of inflammation, increased attention from academia and industry has led to the discovery of new and interesting small-molecule FPR1/FPR2 agonists. Focused attention on the development of appropriate physicochemical and pharmacokinetic profiles is yielding synthesis of new compounds with promising in vivo readouts. This review presents an overview of small-molecule FPR1/FPR2 agonist medicinal chemistry developed over the past 20 years, with a particular emphasis on interrogation in the increasingly sophisticated bioassays which have been developed.
KW - Biased profiles
KW - FPRs
KW - Inflammatory disorders
KW - Small-molecule agonists
KW - Structure-activity relationships
UR - http://www.scopus.com/inward/record.url?scp=85181905245&partnerID=8YFLogxK
U2 - 10.1016/j.ejmech.2023.115989
DO - 10.1016/j.ejmech.2023.115989
M3 - Review Article
C2 - 38199163
AN - SCOPUS:85181905245
SN - 0223-5234
VL - 265
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
M1 - 115989
ER -