Selecting against S1P3 enhances the acute cardiovascular tolerability of 3-(N-benzyl)aminopropylphosphonic acid S1P receptor agonists.
Structurally modified 3-(N-benzylamino)propylphosphonic acid S1P receptor agonists that maintain affinity for S1P1, and have decreased affinity for S1P3 are efficacious, but exhibit decreased acute cardiovascular toxicity in rodents than do nonselective agonists.
Hale
Jeffrey J
JJ
Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA. jeffrey_hale@merck.com
Doherty
George
G
Toth
Leslie
L
Mills
Sander G
SG
Hajdu
Richard
R
Keohane
Carol Ann
CA
Rosenbach
Mark
M
Milligan
James
J
Shei
Gan-Ju
GJ
Chrebet
Gary
G
Bergstrom
James
J
Card
Deborah
D
Forrest
Michael
M
Sun
Shu-Yu
SY
West
Sarah
S
Xie
Huijuan
H
Nomura
Naomi
N
Rosen
Hugh
H
Mandala
Suzanne
S
D000818:Animals; D001593:Benzyl Compounds / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D016466:CHO Cells; D002319:Cardiovascular System / Q000187:drug effects*; D006224:Cricetinae; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008246:Lysophospholipids / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D009206:Myocardium / Q000378:metabolism*; D009943:Organophosphorus Compounds / Q000737:chemistry / Q000494:pharmacology*; D010761:Phosphorus Radioisotopes; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000378:metabolism; D049349:Receptors, Lysosphingolipid / Q000819:agonists* / Q000037:antagonists & inhibitors*; D013110:Sphingosine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology
C495734:3-(N-benzyl)aminopropylphosphonic acid; D001593:Benzyl Compounds; D008246:Lysophospholipids; D009943:Organophosphorus Compounds; D010761:Phosphorus Radioisotopes; D043562:Receptors, G-Protein-Coupled; D049349:Receptors, Lysosphingolipid; D013110:Sphingosine