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ID: ALA1137584
Journal: Bioorg Med Chem Lett
Title: Constrained 7-fluorocarboxychromone-4-aminopiperidine based Melanin-concentrating hormone receptor 1 antagonists: the effects of chirality on substituted indan-1-ylamines.
Authors: Souers AJ, Iyengar RR, Judd AS, Beno DW, Gao J, Zhao G, Brune ME, Napier JJ, Mulhern MM, Lynch JK, Freeman JC, Wodka D, Chen CJ, Falls HD, Brodjian S, Dayton BD, Diaz GJ, Bush EN, Shapiro R, Droz BA, Knourek-Segel V, Hernandez LE, Marsh KC, Reilly RM, Sham HL, Collins CA, Kym PR.
Abstract: The incorporation of constrained tertiary amines into an existing class of N-benzyl-4-aminopiperidinyl chromone-based MCHr1 antagonists led to the identification of a series of chiral racemic compounds that displayed good to excellent functional potency, binding affinity, and selectivity over the hERG channel. Further separation of two distinct chiral racemic compounds into their corresponding pairs of enantiomers revealed a considerable selectivity for MCHr1 for one configuration, in addition to a striking difference in oral exposure between one pair of enantiomers in diet-induced obese mice. Oral administration of the most potent compound in this class in the same animal model led to significant reduction of fat mass in a semi-chronic model for weight loss.
CiteXplore: 17188866