Optimisation of imidazole compounds as selective TAAR1 agonists: discovery of RO5073012.
A series of imidazole compounds has been identified which affords potent and selective partial and full agonists of the TAAR1 receptor. Starting from 2-benzyl-imidazoline screening hits, a series of structurally related 2-benzyl- and 4-benzyl-imidazoles was investigated first, but it proved highly challenging to obtain compounds having sufficient selectivity against the adrenergic alpha 2 receptor. This issue could be successfully addressed by modification of the linker region and SAR exploration led to the discovery of highly selective isopropyl-substituted 4-aminomethyl-imidazole compounds. The work culminated in the identification of the selective TAAR1 partial agonist RO5073012 (4-chlorophenyl)-(1H-imidazol-4-ylmethyl)-isopropyl-amine, 24), which has a good pharmacokinetic profile after oral administration in rodents. RO5073012 has been found to be active in a behavioural rat model which is considered indicative for schizophrenia.
F. Hoffmann-La Roche Ltd, Pharmaceuticals Division, Preclinical Research, CH-4070 Basel, Switzerland. guido.galley@roche.com
Guido
G
Galley
Henri
H
Stalder
Annick
A
Goergler
Marius C
MC
Hoener
Roger D
RD
Norcross
D000284:Administration, Oral; D000814:Aniline Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D006207:Half-Life; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D008861:Microsomes / Q000378:metabolism; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship; D000095383:Trace Amine-Associated Receptors
D000814:Aniline Compounds; D007093:Imidazoles; D043562:Receptors, G-Protein-Coupled; D000095383:Trace Amine-Associated Receptors; C576475:(4-chlorophenyl)-(1H-imidazol-4-ylmethyl)-isopropyl-amine; C029899:imidazole