166096-16-8Relevant articles and documents
Optimisation of imidazole compounds as selective TAAR1 agonists: Discovery of RO5073012
Galley, Guido,Stalder, Henri,Goergler, Annick,Hoener, Marius C.,Norcross, Roger D.
scheme or table, p. 5244 - 5248 (2012/09/07)
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.
Identification of a novel antiangiogenic agent; 4-(N-imidazol-2-ylmethyl)amino benzopyran analogues
Kim, Nakjeong,Lee, Sunkyung,Yi, Kyu Yang,Yoo, Sung-Eun,Kim, Guncheol,Lee, Chong Ock,Park, Sung Hee,Lee, Byung Ho
, p. 1661 - 1663 (2007/10/03)
A series of 4-(N-imidazol-2-ylmethyl)aminobenzopyran analogues, originally designed as KATP openers for ischemic diseases, showed antiangiogenic properties through the inhibition of HUVEC tube formation. Especially one of p-Cl substituted analo
Cardioselective antiischemic ATP-sensitive potassium channel (K(ATP)) openers. 5. Identification of 4-(N-aryl)-substituted benzopyran derivatives with high selectivity
Rovnyak, George C.,Ahmed, Syed Z.,Ding, Charles Z.,Dzwonczyk, Steven,Ferrara, Francis N.,Humphreys, W. Griffith,Grover, Gary J.,Santafianos, Dinos,Atwal, Karnail S.,Baird, Anne J.,McLaughlin, Lee G.,Normandin, Diane E.,Sleph, Paul G.,Traeger, Sarah C.
, p. 24 - 34 (2007/10/03)
This paper describes our studies aimed at the discovery of structurally distinct analogs of the cardioprotective K(ATP) opener BMS-180448 (2) with improved selectivity for the ischemic myocardium. The starting compound 6, derived from the indole analog 4, showed good cardioprotective potency and excellent selectivity compared to 2 and the first-generation K(ATP) opener cromakalim (1). The structure-activity studies indicate that increasing the size of the alkyl ester leads to diminished potency as does its replacement with a variety of other groups (nitrile, methyl sulfone). Replacement of the ethyl ester of 6 with an imidazole gave the best compound 3 (BMS-191095) of this series which maintains the potency and selectivity of its predecessor 6. The results described in this publication further support that there is no correlation between vasorelaxant and cardioprotective potencies of K(ATP) openers. Compound 3 is over 20- and 4000-fold more selective for the ischemic myocardium than 2 and cromakalim (1), respectively. The selectivity for the ischemic myocardium is achieved by reduction of vasorelaxant potency rather than enhancement in antiischemic potency. As for cromakalim (1) and 2, the cardioprotective effects of compound 3 are inhibited by cotreatment with the K(ATP) blocker glyburide, indicating that the K(ATP) opening is involved in its mechanism of cardioprotection. With its good oral bioavailability (47%) and plasma elimination half-life (3 h) in rats, compound 3 offers an excellent candidate to investigate the role of residual vasorelaxant potency of 2 toward its cardioprotective activity in vivo.
