Discovery of a novel series of potent S1P1 agonists.
The discovery of a novel series of S1P1 agonists is described. Starting from a micromolar HTS positive, iterative optimization gave rise to several single-digit nanomolar S1P1 agonists. The compounds were able to induce internalization of the S1P1 receptor, and a selected compound was shown to be able to induce lymphopenia in mice after oral dosing.
Crosignani
Stefano
S
Merck Serono SA, 9 Chem. des Mines, 1202 Geneva, Switzerland. stefano.crosignani@merckserono.net
Bombrun
Agnes
A
Covini
David
D
Maio
Maurizio
M
Marin
Delphine
D
Quattropani
Anna
A
Swinnen
Dominique
D
Simpson
Don
D
Sauer
Wolfgang
W
Françon
Bernard
B
Martin
Thierry
T
Cambet
Yves
Y
Nichols
Anthony
A
Martinou
Isabelle
I
Burgat-Charvillon
Fabienne
F
Rivron
Delphine
D
Donini
Cristina
C
Schott
Olivier
O
Eligert
Valerie
V
Novo-Perez
Laurence
L
Vitte
Pierre-Alain
PA
Arrighi
Jean-François
JF
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D055808:Drug Discovery; D000068876:Fingolimod Hydrochloride; D057166:High-Throughput Screening Assays; D006801:Humans; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D011409:Propylene Glycols / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D049349:Receptors, Lysosphingolipid / Q000819:agonists* / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D011409:Propylene Glycols; D049349:Receptors, Lysosphingolipid; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine