Part I: Structure-activity relationship of human glutaminyl cyclase inhibitors having an N-(5-methyl-1H-imidazol-1-yl)propyl thiourea template. Part II: α-Substituted 2-(3-Fluoro-4-methylsulfonamidophenyl)acetamides as Potent TRPV1 Antagonists.
Part I: Glutaminyl cyclase 저해제로 N-(5-methyl-1H-imidazol-1-yl)propyl thiourea 골격계 화합물의 구조-활성 연구. Part II: 강력한 TRPV1 길항제로서 α-Substituted 2-(3-Fluoro-4-methylsulfonamidophenyl)acetamides 화합물의 연구.
- 트란 프엉 타오
- 약학대학 약학과
- Issue Date
- 서울대학교 대학원
- Glutaminyl cyclase QC; Alzheimer’s disease; Enzyme inhibitor; TRPV1 Antagonist; Analgesis; Capsaicin; Molecular Modeling.
- 학위논문 (박사)-- 서울대학교 대학원 : 약학과 약품화학전공, 2015. 8. 이지우.
- PART II: α-Substituted 2-(3-Fluoro-4-methylsulfonamidophenyl)-acetamides as Potent TRPV1 Antagonists.
The transient receptor potential vanilloid 1 channel (TRPV1) has emerged as a very promising therapeutic target, reflecting its central role in nociception and its involvement in a range of diseases. Capsaicin and resiniferatoxin provided early structural leads for understanding the vanilloid pharmacophore, and it was soon recognized that appropriately modified derivatives were able to achieve antagonism. Of particular importance, hyperthermia represents a common side effect of TRPV1 antagonists and the pattern of antagonistic activities for different agonists has been suggested to be related to the ability of an antagonist to cause hyperthermia. Further, different antagonists are differentially affected by the signaling pathways that regulate TRPV1. The availability of novel antagonists will be critical for optimizing such characteristics.
The structure of capsaicin (CAP) has been divided into three pharmacophoric regions. Correspondingly, the antagonistic template was subdivided into the same three pharmacophoric regions, namely the A-region (3-fluoro-4-methylsulfon amidophenyl), the B-region (propanamide), and the C-region ((6-trifluoromethyl-pyridin-3-yl)methyl).
In order to gain better positioning of the C-region with the receptor through α-substitution in the B-region, with consequent enhancement of activity, we have extensively investigated the structure activity relationships of α-substituted acetamide derivatives for hTRPV1 antagonism. We describe incorporation of various alkyl, dialkyl and aryl groups at the α-position in the B-region, with 4-methylpiperidinyl and cyclohexylthio groups at the 2-position in the pyridine C-region, and we have evaluated their antagonism of CAP stimulation of hTRPV1 expressed in CHO cells.