Paul Ornstein - Synthesis and evaluation of a series of novel 2-((4-chlorophenoxy)methyl)-benzimidazoles as selective neuropeptide Y Y1 receptor antagonists

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  Zarrinmayeh, Hamideh, Nunes, Anne M., Ornstein, Paul L.,   Zimmerman, Dennis M., Arnold, M. Brian, Schober, Douglas A.,   Gackenheimer, Susan L., Bruns, Robert F., Hipskind, Philip A.,   Britton, Thomas C., Cantrell, Buddy E., Gehlert, Donald R.   Journal of Medicinal Chemistry 1998  41 (15) 2709-2719

  Abstract: A series of novel benzimidazoles (BI)   derived from the indole 2 was synthesized and evaluated as   selective neuropeptide Y (N-PY) Y1 receptor antagonists with the   aim of developing antiobesity drugs. In our SAR approach, the   (4-chlorophenoxy)methyl group at C-2 was kept constant and a   series of BIs substituted with various piperidinylalkyl groups at   N-1 was synthesized to identify the optimal spacing and   orientation of the piperidine ling nitrogen relative to the   benzimidazole. The 3-(3-piperidinyl)propyl in 33 was found to   maximize affinity for the Y1 receptor. Because of the critical   importance of Arg33 and Arg35 of NPY binding to the Y1 receptor,   the incorporation of an additional aminoalkyl functionality to   the structure of 33 was explored. Methyl substitution was used to   probe where substitution on the aromatic ring was best tolerated.   In this fashion, the C-4 was chosen for the substitution of the   second aminoalkyl functionality. Synthesis of such compounds with   a phenoxy tether using the 4-hydroxybenzimidazole 11 was pursued   because of their relative ease of synthesis. Functionalization of   the hydroxy group of 45 with a series of piperidinylalkyl groups   provided the dibasic benzimidazoles 55-62. Among them, BI 56   demonstrated a Ki of 0.0017 muM, which was 400-fold more potent   than 33. To evaluate if there was a stereoselective effect on   affinity for these BIs, the four constituent stereoisomers   (69-72) of the BI 60 were prepared using the S- and R-isomers of   bromide 17. Antagonist activity of these BIs was confirmed by   measuring the ability of selected compounds to reverse   NPY-induced forskolin-stimulated cyclic AMP. The high selectivity   of several BI antagonists for the Y1 versus Y2, Y4, and Y5   receptors was also shown.

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