title: Discovery of a novel class of zwitterionic, potent, selective and orally active S1P₁ direct agonists.
abstract: Amido-1,3,4-thiadiazoles have been identified as a novel structural class of potent and selective sphingosine-1-phosphate receptor subtype 1 agonists. Starting from a micromolar HTS hit with the help of an in-house homology model, robust structural-activity relationships were developed to yield compounds with good selectivity and excellent in vivo efficacy in rat models.
authors.affiliation: Almirall Research Center, Laboratorios Almirall SA, Ctra. Laureà Miró 408, E-08980 Sant Feliu de Llobregat, Barcelona, Spain. nuria.aguilar@almirall.com
authors.forename: Nuria
authors.initials: N
authors.lastname: Aguilar
authors.forename: Marta
authors.initials: M
authors.lastname: Mir
authors.forename: Pedro M
authors.initials: PM
authors.lastname: Grima
authors.forename: Manel
authors.initials: M
authors.lastname: López
authors.forename: Victor
authors.initials: V
authors.lastname: Segarra
authors.forename: Laia
authors.initials: L
authors.lastname: Esteban
authors.forename: Imma
authors.initials: I
authors.lastname: Moreno
authors.forename: Nuria
authors.initials: N
authors.lastname: Godessart
authors.forename: Gema
authors.initials: G
authors.lastname: Tarrasón
authors.forename: Teresa
authors.initials: T
authors.lastname: Domenech
authors.forename: Dolors
authors.initials: D
authors.lastname: Vilella
authors.forename: Clara
authors.initials: C
authors.lastname: Armengol
authors.forename: Mònica
authors.initials: M
authors.lastname: Córdoba
authors.forename: Mar
authors.initials: M
authors.lastname: Sabaté
authors.forename: Daniel
authors.initials: D
authors.lastname: Casals
authors.forename: Maria
authors.initials: M
authors.lastname: Domínguez
mesh_terms: D000284:Administration, Oral; D000818:Animals; D018360:Crystallography, X-Ray; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy; D008231:Lymphopenia / Q000097:blood; D008958:Models, Molecular; D015394:Molecular Structure; D051381:Rats; D049349:Receptors, Lysosphingolipid / Q000819:agonists*; D000081025:Sphingosine-1-Phosphate Receptors; D013329:Structure-Activity Relationship; D013830:Thiadiazoles / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*
chemical_list: D049349:Receptors, Lysosphingolipid; C578616:S1PR1 protein, rat; D000081025:Sphingosine-1-Phosphate Receptors; D013830:Thiadiazoles; C058949:1,3,4-thiadiazole