2. Academic Validation
  3. Discovery of 12 (BMS-986172) as a Highly Potent MGAT2 Inhibitor that Achieved Targeted Efficacious Exposures at a Low Human Dose for the Treatment of Metabolic Disorders

Discovery of 12 (BMS-986172) as a Highly Potent MGAT2 Inhibitor that Achieved Targeted Efficacious Exposures at a Low Human Dose for the Treatment of Metabolic Disorders

  • J Med Chem. 2023 Sep 28;66(18):13135-13147. doi: 10.1021/acs.jmedchem.3c01147.
Wei Meng,  Robert Brigance,  James Mignone,  Lidet Negash,  Guohua Zhao,  Saleem Ahmad,  Wei Wang,  Fang Moore,  Xiang-Yang Ye,  Jung-Hui Sun,  Arvind Mathur,  Yi-Xin Li,  Anthony Azzara,  Zhengping Ma,  Ching-Hsuen Chu,  Mary Jane Cullen,  Suzanne Rooney,  Susan Harvey,  Lisa Kopcho,  Lynn Abell,  Kevin O'Malley,  William Keim,  Elizabeth A Dierks,  Shu Chang,  Kimberly A Foster,  David Harden,  Marta Dabros,  Vineet Goti,  Claudia De Oliveira,  Gopal Krishna,  Mary Ann Pelleymounter,  Jean Whaley,  Jeffrey A Robl,  Dong Cheng,  Pratik Devasthale
PMID: 37724542 DOI: 10.1021/acs.jmedchem.3c01147
Abstract

A series of dihydropyridinone (DHP) compounds was prepared and evaluated for MGAT2 activity. The efforts led to the identification of novel tetrazolones with potent MGAT2 inhibitory activity and favorable in vitro profiles. Further tests of select analogues in mouse models revealed significant reduction in food intake and body weight. Subsequent studies in MGAT2 knockout mice with the lead candidate 12 (BMS-986172) showed on-target- and mechanism-based pharmacology. Moreover, its favorable pharmacokinetic (PK) profile and the lack of species variability in the glucuronidation potential resulted in a greater confidence level in the projection of a low dose for achieving targeted efficacious exposures in humans. Consistent with these projections, PK data from a phase 1 trial confirmed that targeted efficacious exposures could be achieved at a low dose in humans, which supported compound 12 as our second and potentially superior development candidate for the treatment of various metabolic disorders.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z