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Improving metabolic stability with deuterium: The discovery of HWL ‐066, a potent and long‐acting free fatty acid receptor 1 agonists
Author(s) -
Liu Chunxia,
Li Zheng,
Shi Wei,
Li Huilan,
Wang Nasi,
Dai Yuxuan,
Liao Chen,
Huang Wenlong,
Qian Hai
Publication year - 2018
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.13321
Subject(s) - chemistry , agonist , receptor , glibenclamide , medicine , endocrinology , fatty acid , beta oxidation , pharmacology , diabetes mellitus , biochemistry
The free fatty acid receptor 1 ( FFA 1) is a potential target due to its function in enhancing of glucose‐stimulated insulin secretion. The FFA 1 agonist GW 9508 has great potential for the treatment of type 2 diabetes mellitus, but it has been suffering from high plasma clearance probably because the phenylpropanoic acid is vulnerable to β‐oxidation. To identify orally available analog without influence on the unique pharmacological mechanism of GW 9508, we tried to interdict the metabolically labile group by incorporating two deuterium atoms at the α‐position of phenylpropionic acid affording compound 4 ( HWL ‐066). As expected, HWL ‐066 revealed a lower clearance ( CL = 0.23 L −1 hr −1 kg −1 ), higher maximum concentration ( C max = 5907.47 μg/L), and longer half‐life ( T 1/2 = 3.50 hr), resulting in a 2.8‐fold higher exposure than GW 9508. Moreover, the glucose‐lowering effect of HWL ‐066 was far better than that of GW 9508 and comparable with TAK ‐875. Different from glibenclamide, no side‐effect of hypoglycemia was observed in mice after oral administrating HWL ‐066 (80 mg/kg).