Synthesis and evaluation of benzothiazole-based analogues as novel, potent, and selective fatty acid amide hydrolase inhibitors.
High-throughput screening (HTS) identified benzothiazole analogue 3 as a potent fatty acid amide hydrolase (FAAH) inhibitor. Structure-activity relationship (SAR) studies indicated that the sulfonyl group, the piperidine ring and benzothiazole were the key components to their activity, with 16j being the most potent analogue in this series. Time-dependent preincubation study of compound 3 was consistent with it being a reversible inhibitor. Activity-based protein-profiling (ABPP) evaluation of 3 in rat tissues revealed that it had exceptional selectivity and no off-target activity with respect to other serine hydrolases. Molecular shape overlay of 3 with a known FAAH inhibitor indicated that these compounds might act as transition-state analogues, forming putative hydrogen bonds with catalytic residues and mimicking the charge distribution of the tetrahedral transition state. The modeling study also indicated that hydrophobic interactions of the benzothiazole ring with the enzyme contributed to its extraordinary potency. These compounds may provide useful tools for the study of FAAH and the endocannabinoid system.
Wang
Xueqing
X
Neuroscience Research, Global Pharmaceutical Research and Development, AP10/303, Abbott Laboratories, Abbott Park, Illinois 60064, USA. xueqing.wang@abbott.com
Sarris
Katerina
K
Kage
Karen
K
Zhang
Di
D
Brown
Scott P
SP
Kolasa
Teodozyi
T
Surowy
Carol
C
El Kouhen
Odile F
OF
Muchmore
Steven W
SW
Brioni
Jorge D
JD
Stewart
Andrew O
AO
D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D052160:Benzothiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D015394:Molecular Structure; D009928:Organ Specificity / Q000187:drug effects; D011485:Protein Binding; D051381:Rats; D013329:Structure-Activity Relationship; D013997:Time Factors; D000099252:Fatty Acid Amide Hydrolases
D000581:Amidohydrolases; D052160:Benzothiazoles; D004791:Enzyme Inhibitors; D000099252:Fatty Acid Amide Hydrolases; C005465:benzothiazole