Table 4.
Inhibitors of KP enzymes tested in preclinical models of brain disorders.
| Inhibitors | Names | Structural Formula | Indications | Comments |
|---|---|---|---|---|
| IDO inhibitors | 1-methyl-l-tryptophan (L-1-MT) |
|
Depression/Preclinical [187] | Poor pharmacokinetics [188]; Competitive inhibitor [189]. |
| Coptisine |
|
AD/Preclinical | Noncompetitive inhibitor. Potent inhibitor of recombinant human IDO [183]. |
|
| TDO inhibitors | 68OC91 |
|
Cognitive deficits and anxiety/Preclinical | Potent inhibitor without influencing 5-HT reuptake. Poor solubility and bioavailability [190]. |
| Allopurinol |
|
Stress/Preclinical | Uncertain about structure and lack of clinical trials [190]. | |
| (S)-4-(ethylsulfonyl)benzoyl Alanine (S-ESBA) |
|
Neurodegenerative and Cognitive disorders/Preclinical [191] | KATII selective. Lowers the KYNA level in the rat brain [192]; Low activity against human KATII [19]. |
|
| KATII inhibitors | BFF-122 |
|
Neurodegenerative and Cognitive disorders/Preclinical [191] | Irreversible KATII inhibitor. Irreversible PLP deactivators [191]. |
| PF-04859989 |
|
Neurodegenerative and Cognitive disorders/Preclinical [191] | Strong therapeutic effect in the rat. BBB permeable [192]. |
|
| ZINC35466084 |
|
Experimental/laboratory phase | Potent inhibitor [193]. | |
| JN-01 and JN-02 | No information | Experimental/laboratory phase | Potent inhibitor [194] | |
| KMO inhibitors | UPF-648 |
|
Neuropathy/Preclinical [107] | Acts as an effector molecule of KMO. Reduction of flavin by NADPH. Generating the cytotoxic H2O2 [195]. |
| Ro 61-8048 |
|
Neurodegenerative or neurologic disorders/Preclinical [196] | Competitive inhibitor [197]; Poor penetration of BBB in rats [195]. |
|
| CHDI-340246 |
|
HD/Preclinical | No therapeutic efficacy in a mouse model of HD [198]. |
Abbreviations: 5-HT, 5-hydroxytryptophan; AD, Alzheimer’s disease; BBB: blood-brain barrier; CNS, central nervous system; HD, Huntington disease; IDO, indoleamine-2,3-dioxygenase; KAT, kynurenine aminotransferase I-III; KMO, kynurenine 3-monooxygenase; KP, kynurenine pathway; KYNA, kynurenic acid; PPP, pyridoxal-51-phosphate; TDO, tryptophan-2,3-dioxygenase.