Delving into the Latest Updates on LY-280748 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

LTB4R

Mechanism

LTB4R antagonists(Leukotriene B4 receptor antagonists)

Therapeutic Areas

Immune System DiseasesRespiratory DiseasesSkin and Musculoskeletal Diseases

Active Indication-

Inactive Indication

ArthritisAsthmaPsoriasis

Originator Organization

Eli Lilly & Co.

Active Organization-

Inactive Organization

Eli Lilly & Co.

Drug Highest PhasePendingDiscovery

First Approval Date-

Regulation-

Leukotriene B₄ (LTB₄) is an important mediator of inflammatory cell function and has been implicated as a pro-inflammatory agent in asthma, inflammatory bowel disease, psoriasis and arthritis.A novel class of potent and orally active LTB₄ receptor antagonists having the 1,2,4,5-substituted phenol core structure is reported.The effect of the ortho-phenol substituent on human neutrophil and guinea pig lung membrane receptor binding, as well as on in vitro antagonism of the LTB₄-induced human neutrophil CD11b/CD18 integrin up-regulation and guinea pig parenchyma tissue contraction, was studied for compounds containing a 6-methyl-6-(2H-tetrazol-5-yl)heptyloxy acid side chain.Compound I (R = Ph) (10a, LY280748), having an o-Ph substituent, is superior to antagonists with either o-acetyl, -alkyl, or -alkoxy substituents.Schild anal. of 10a demonstrated pure competitive antagonism against LTB₄ in guinea pig parenchyma with a pA₂ of 8.46 and a slope of -1.06 ± 0.12.Examination of how substituents on this appended o-Ph ring affect receptor binding revealed that a p-fluoro substituent (I; R = p-FC₆H₄) (10e, LY306669) was optimal for both binding to human neutrophil receptors (IC₅₀ = 2.8 nM) and guinea pig lung membrane receptors (IC₅₀ = 3.69 ± 1.02 nM).Compound 10e was also very effective at antagonizing the CD11b/CD18 integrin up-regulation in human neutrophils (IC₅₀ = 13.1 ± 0.54 nM) and guinea pig parenchyma tissue contraction (pK_B = 8.34 ± 0.19).10E was very potent in vivo at inhibiting the measured gas trapping response (ED₅₀ = 0.03 mg/kg, i.v. and ED₅₀ = 0.56 mg/kg, p.o.).

100 Deals associated with LY-280748

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