title: Discovery of novel and potent leukotriene B4 receptor antagonists. Part 1.
abstract: The inhibition of LTB(4) binding to and activation of G-protein-coupled receptors BLT1 and BLT2 is the premise of a treatment for several inflammatory diseases. In a lead optimization effort starting with the leukotriene B(4) (LTB(4)) receptor antagonist (2), members of a series of 3,5-diarylphenyl ethers were found to be highly potent inhibitors of LTB(4) binding to BLT1 and BLT2 receptors, with varying levels of selectivity depending on the substitution. In addition, compounds 33 and 38 from this series have good in vitro ADME properties, good oral bioavailability, and efficacy after oral delivery in guinea pig LTB(4) and nonhuman primate allergen challenge models. Further profiling in a rat non-GLP toxicity experiment provided the rationale for differentiation and selection of one compound (33) for clinical development.
authors.affiliation: Department of Discovery Chemistry, Roche Research Center, 340 Kingsland Street, Nutley, New Jersey 07110-1199, USA. robert.goodnow@roche.com
authors.forename: Robert A
authors.initials: RA
authors.lastname: Goodnow
authors.forename: Alexandra
authors.initials: A
authors.lastname: Hicks
authors.forename: Achyutharao
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authors.lastname: Sidduri
authors.forename: Agnieszka
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authors.lastname: Kowalczyk
authors.forename: Romyr
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authors.lastname: Dominique
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authors.lastname: Gillespie
authors.forename: Nader
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authors.lastname: Tilley
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authors.forename: Gary
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authors.lastname: Cavallo
authors.forename: Shahid A
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authors.forename: Jessica D
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authors.lastname: Ventre
authors.forename: Danielle
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authors.lastname: Lavelle
authors.forename: Nadine S
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authors.lastname: Tare
authors.forename: Hyesun
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authors.lastname: Oh
authors.forename: Martin
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authors.lastname: Lamb
authors.forename: Grazyna
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authors.lastname: Kurylko
authors.forename: Rachid
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authors.forename: Matthew B
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authors.lastname: Wright
authors.forename: Anjula
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authors.lastname: Pamidimukkala
authors.forename: Thomas
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authors.lastname: Egan
authors.forename: Ueli
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authors.lastname: Gubler
authors.forename: Ann F
authors.initials: AF
authors.lastname: Hoffman
authors.forename: Xin
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authors.lastname: Wei
authors.forename: Ying L
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authors.lastname: Li
authors.forename: John
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authors.lastname: O'Neil
authors.forename: Ruben
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authors.lastname: Marcano
authors.forename: Karen
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authors.lastname: Pozzani
authors.forename: Tina
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authors.lastname: Molinaro
authors.forename: Jennifer
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authors.lastname: Santiago
authors.forename: Laura
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authors.lastname: Singer
authors.forename: Maureen
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authors.lastname: Hargaden
authors.forename: David
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authors.lastname: Moore
authors.forename: A Robert
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authors.lastname: Catala
authors.forename: Lisa C F
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authors.lastname: Chao
authors.forename: Gesine
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authors.lastname: Hermann
authors.forename: Radhika
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authors.lastname: Venkat
authors.forename: Helena
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authors.lastname: Mancebo
authors.forename: Louis M
authors.initials: LM
authors.lastname: Renzetti
mesh_terms: D000818:Animals; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D006168:Guinea Pigs; D018922:HL-60 Cells; D006801:Humans; D020024:Leukotriene Antagonists / Q000737:chemistry* / Q000494:pharmacology; D010647:Phenyl Ethers / Q000737:chemistry / Q000494:pharmacology*; D011323:Primates; D011485:Protein Binding; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D018102:Receptors, Leukotriene B4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C513240:LTB4R protein, human; C485878:LTB4R2 protein, human; D020024:Leukotriene Antagonists; D010647:Phenyl Ethers; D043562:Receptors, G-Protein-Coupled; D018102:Receptors, Leukotriene B4