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Bioorg Med Chem Lett. 2012 Aug 15;22(16):5244-8. doi: 10.1016/j.bmcl.2012.06.060. Epub 2012 Jun 23.

Optimisation of imidazole compounds as selective TAAR1 agonists: discovery of RO5073012.

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F. Hoffmann-La Roche Ltd, Pharmaceuticals Division, Preclinical Research, CH-4070 Basel, Switzerland.


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.

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