Development of Novel Mitochondrial Pyruvate Carrier Inhibitors to Treat Hair Loss.
J Med Chem
; 64(4): 2046-2063, 2021 02 25.
Article
in En
| MEDLINE
| ID: mdl-33534563
ABSTRACT
Herein, we report the synthesis and evaluation of novel analogues of UK-5099 both in vitro and in vivo for the development of mitochondrial pyruvate carrier (MPC) inhibitors to treat hair loss. A comprehensive understanding of the structure-activity relationship was obtained by varying four positions of the hit compound, namely, the alkyl group on the N1 position, substituents on the indole core, various aromatic and heteroaromatic core structures, and various Michael acceptors. The major discovery was that the inhibitors with a 3,5-bis(trifluoromethyl)benzyl group at the N1 position were shown to have much better activity than JXL001 (UK-5099) to increase cellular lactate production. Additionally, analogue JXL069, possessing a 7-azaindole heterocycle, was also shown to have significant MPC inhibition activity, which further increases the chemical space for drug design. Finally, more than 10 analogues were tested on shaved mice by topical treatment and promoted obvious hair growth on mice.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Acrylates
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Monocarboxylic Acid Transporters
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Mitochondrial Membrane Transport Proteins
/
Alopecia
/
Indoles
Limits:
Animals
Language:
En
Journal:
J Med Chem
Journal subject:
QUIMICA
Year:
2021
Document type:
Article
Affiliation country:
Estados Unidos