Pharmacophore-based design of novel oxadiazoles as selective sphingosine-1-phosphate (S1P) receptor agonists with in vivo efficacy.
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 S1P1 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 S1P1,5 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, S1P1,5 agonist 49 demonstrated comparable efficacy while S1P1 -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.
Chemistry Department, Merck Serono S.A. 9 Chemin des Mines, 1202 Geneva (Switzerland); Present Address: Asceneuron S.A., EPFL Innovation Park, 1015 Lausanne (Switzerland). anna.quattropani@asceneuron.com.
Anna
A
Quattropani
Wolfgang H B
WH
Sauer
Stefano
S
Crosignani
Jerome
J
Dorbais
Patrick
P
Gerber
Jerome
J
Gonzalez
Delphine
D
Marin
Mathilde
M
Muzerelle
Fanny
F
Beltran
Anthony
A
Nichols
Katrin
K
Georgi
Manfred
M
Schneider
Pierre-Alain
PA
Vitte
Valerie
V
Eligert
Laurence
L
Novo-Perez
Jennifer
J
Hantson
Sebastien
S
Nock
Susanna
S
Carboni
Adriano Luis Soares
AL
de Souza
Jean-François
JF
Arrighi
Ursula
U
Boschert
Agnes
A
Bombrun
D000818:Animals; D015195:Drug Design; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000276:immunology; D005260:Female; D006801:Humans; D007155:Immunologic Factors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D009103:Multiple Sclerosis / Q000188:drug therapy; D010069:Oxadiazoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D049349:Receptors, Lysosphingolipid / Q000819:agonists* / Q000276:immunology; D013329:Structure-Activity Relationship
D007155:Immunologic Factors; D010069:Oxadiazoles; D049349:Receptors, Lysosphingolipid
FTY-720 (fingolimod); agonists; drug design; immunomodulators; sphingosine-1-phosphate receptors; structure-activity relationships