Discovery of novel and potent leukotriene B4 receptor antagonists. Part 1.
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.
Goodnow
Robert A
RA
Department of Discovery Chemistry, Roche Research Center, 340 Kingsland Street, Nutley, New Jersey 07110-1199, USA. robert.goodnow@roche.com
Hicks
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Sidduri
Achyutharao
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Kowalczyk
Agnieszka
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Dominique
Romyr
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Qiao
Qi
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Lou
Jian Ping
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Gillespie
Paul
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Fotouhi
Nader
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Tilley
Jefferson
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Cohen
Noal
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Choudhry
Satish
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Cavallo
Gary
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Tannu
Shahid A
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Ventre
Jessica D
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Lavelle
Danielle
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Tare
Nadine S
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Hyesun
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Lamb
Martin
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Kurylko
Grazyna
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Hamid
Rachid
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Wright
Matthew B
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Pamidimukkala
Anjula
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Egan
Thomas
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Gubler
Ueli
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Hoffman
Ann F
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Wei
Xin
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Li
Ying L
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O'Neil
John
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Marcano
Ruben
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Pozzani
Karen
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Molinaro
Tina
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Santiago
Jennifer
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Singer
Laura
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Hargaden
Maureen
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David
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Catala
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Chao
Lisa C F
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Hermann
Gesine
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Venkat
Radhika
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Mancebo
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Renzetti
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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
C513240:LTB4R protein, human; C485878:LTB4R2 protein, human; D020024:Leukotriene Antagonists; D010647:Phenyl Ethers; D043562:Receptors, G-Protein-Coupled; D018102:Receptors, Leukotriene B4