Author: Robl, Jeffrey A ; Bhaskaran, Selvakumar ; Mahammad, Shahe ; Shah, Devang Praful ; Patankar, Vidya ; Mandal, Umasankar ; A M Subbaiah, Murugaiah ; Murphy, Brian J ; Rami, Bhadresh ; Huang, Christine ; Nutakki, Ravikumar ; Washburn, William N

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.

13 Oct 2016·Journal of Medicinal ChemistryQ1 · MEDICINE

Synthesis and Antiobesity Properties of 6-(4-Chlorophenyl)-3-(4-((3,3-difluoro-1-hydroxycyclobutyl)methoxy)-3-methoxyphenyl)thieno[3,2-d]pyrimidin-4(3H)-one (BMS-814580): A Highly Efficacious Melanin Concentrating Hormone Receptor 1 (MCHR1) Inhibitor

Q1 · MEDICINE

Article

Author: Azzara, Anthony V. ; Rooney, Suzanne ; Janovitz, Evan B. ; Ahmad, Saleem ; Harvey, Susan ; Wang, Wei ; Hernandez, Andres S. ; Thomas, Michael ; Rohrbach, Kenneth ; Washburn, William N. ; Ngu, Khehyong ; Robl, Jeffrey A. ; Pelleymounter, Mary Ann ; Murphy, Brian J. ; Huang, Christine ; Longhi, Daniel ; Gemzik, Brian ; Flynn, Neil ; Zhang, Hongwei ; Zhang, Lisa ; Devenny, James ; Glick, Susan ; Bisaha, Sharon ; Godonis, Helen

The potent MCHR1 in vitro and in vivo antagonist activity of a series of cyclic tertiary alcohols derived from compound 2b is described. Subsequent pharmacokinetic and pharmacodynamic studies identified BMS-814580 (compound 10) as a highly efficacious antiobesity agent with a relatively clean in vitro and in vivo safety profile.

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Indication	Highest Phase	Country/Location	Organization	Date
Obesity	Preclinical	United States	Bristol Myers Squibb Co.	-

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