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Pharmacophore‐Based Design of Novel Oxadiazoles as Selective Sphingosine‐1‐phosphate (S1P) Receptor Agonists with in vivo Efficacy
Author(s) -
Quattropani Anna,
Sauer Wolfgang H. B.,
Crosignani Stefano,
Dorbais Jerome,
Gerber Patrick,
Gonzalez Jerome,
Marin Delphine,
Muzerelle Mathilde,
Beltran Fanny,
Nichols Anthony,
Georgi Katrin,
Schneider Manfred,
Vitte PierreAlain,
Eligert Valerie,
NovoPerez Laurence,
Hantson Jennifer,
Nock Sebastien,
Carboni Susanna,
de Souza Adriano Luis Soares,
Arrighi JeanFrançois,
Boschert Ursula,
Bombrun Agnes
Publication year - 2015
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201402557
Subject(s) - agonist , sphingosine 1 phosphate receptor , chemistry , pharmacology , receptor , in vivo , trifluoromethyl , stereochemistry , sphingosine 1 phosphate , sphingosine , biochemistry , biology , organic chemistry , alkyl , microbiology and biotechnology
Abstract Sphingosine‐1‐phosphate (S1P) receptor agonists have shown promise as therapeutic agents for multiple sclerosis (MS) due to their regulatory roles within the immune, central nervous system, and cardiovascular system. Here, the design and optimization of novel [1,2,4]oxadiazole derivatives as selective S1P receptor agonists are described. The structure–activity relationship exploration was carried out on the three dominant segments of the series: modification of the polar head group (P), replacement of the oxadiazole linker (L) with different five‐membered heterocycles, and the use of diverse 2,2′‐disubstituted biphenyl moieties as the hydrophobic tail (H). All three segments have a significant impact on potency, S1P receptor subtype selectivity, physicochemical properties, and in vitro absorption, distribution, metabolism, excretion and toxicity (ADMET) profile of the compounds. From these optimization studies, a selective S1P 1 agonist, N ‐methyl‐ N ‐(4‐{5‐[2‐methyl‐2′‐(trifluoromethyl)biphenyl‐4‐yl]‐1,2,4‐oxadiazol‐3‐yl}benzyl)glycine ( 45 ), and a dual S1P 1,5 agonist, N ‐methyl‐ N ‐(3‐{5‐[2′‐methyl‐2‐(trifluoromethyl)biphenyl‐4‐yl]‐1,2,4‐oxadiazol‐3‐yl}benzyl)glycine ( 49 ), emerged as frontrunners. These compounds distribute predominantly in lymph nodes and brain over plasma and induce long lasting decreases in lymphocyte count after oral administration. When evaluated head‐to‐head in an experimental autoimmune encephalomyelitis mouse model, together with the marketed drug fingolimod, a pan‐S1P receptor agonist, S1P 1,5 agonist 49 demonstrated comparable efficacy while S1P 1 ‐selective agonist 45 was less potent. Compound 49 is not a prodrug, and its improved property profile should translate into a safer treatment of relapsing forms of MS.