%0 Journal Article
%T Exploring monocyclic core: Discovery of pyrrol-2-one derivatives as a new series of potent MCHR1 antagonists with in vivo efficacy.
%A A M Subbaiah M
%A Mandal U
%A Patankar V
%A Bhaskaran S
%A Nutakki R
%A Rami B
%A Shah DP
%A Mahammad S
%A Murphy BJ
%A Huang C
%A Robl JA
%A Washburn WN
%J Eur J Med Chem
%V 276
%N 0
%D 2024 Oct 5
%M 39053192
%F 7.088
%R 10.1016/j.ejmech.2024.116686
%X With an objective to improve the profiles of the 1st generation non-basic MCHR1 antagonists, a lean design approach of replacing the bicyclic thienopyrimidine core with a monocyclic pyrrol-2-one chemotype was examined in the context of reducing aromatic ring count, while also contemplating enhanced flexibility as a means of decreasing flat character. The new compounds exhibited potent antagonism up to the sub-nanomolar range, thereby implying that the monocyclic ring could effectively serve as an effective bioisostere of the bicyclic system. The prototype compound 2m offered benefits like improved potency, reduced half-life, and enhanced solubility, while also demonstrating >5% reduction in weight gain in rats, thereby providing proof-of-concept for this new class of compounds as anti-obesity agents.