GDC-6599 is an orally active TRPA1 inhibitor, with IC50 values of 5.3 nM in humans, 6.6 nM in rats, 9.3 nM in dogs, 7.2 nM in monkeys, and 15 nM in guinea pigs. GDC-6599 can be used in the research of neuropathic pain and respiratory diseases such as asthma and chronic cough[1].
in vivo
GDC-6599 (rat: 0-100 mg/kg, cynomolgus monkey: 0, 15, 50 mg/kg (male) and 30 mg/kg (female); once daily; 7 days; p.o.) has low preclinical toxicity and reduces aldehyde oxidase metabolism risk in rats and crab eating macaques[1].
GDC-6599 (0-3 mg/kg; p.o.) can reduce skin blood flow induced by local application (applied to the right ear) of TRPA1 agonist allyl isothiocyanate (AITC) in male Dunkin Hartley guinea pigs[1].
GDC-6599 (0-3 mg/kg; p.o.) can inhibit cough response in guinea pig cough model induced by cinnamaldehyde[1].
Animal Model:
Sprague-Dawley and Wistar Han IGS rats, respectively, 8-14 weeks of age[1].
Dosage:
0-100 mg/kg
Administration:
Oral gavage (p.o.); once daily; 7 days
Result:
Extended prothrombin time (PT) and activated partial thromboplastin time (aPTT).
Animal Model:
Cynomolgus monkey[1].
Dosage:
0, 15, 50 mg/kg (male) and 30 mg/kg (female)
Administration:
Oral gavage (p.o.); once daily; 7 days
Result:
Extended coagulation parameters.
Animal Model:
Male Dunkin-Hartley guinea pigs (8 weeks old)[1].
Dosage:
0-3 mg/kg
Administration:
Oral gavage (p.o.); were dosed 75 min prior to imaging
Result:
Inhibited blood perfusion, prolonged perfusion time, and reduced maximum perfusion level.
Animal Model:
Cinnamaldehyde induced cough model in guinea pigs[1].
Dosage:
0-3 mg/kg
Administration:
Oral gavage (p.o.)
Result:
Reduced the frequency of coughing.
References
[1] Terrett JA, et al. Discovery of TRPA1 Antagonist GDC-6599: Derisking Preclinical Toxicity and Aldehyde Oxidase Metabolism with a Potential First-in-Class Therapy for Respiratory Disease. J Med Chem. 2024 Mar 14;67(5):3287-3306. doi: 10.1021/acs.jmedchem.3c02121. Epub 2024 Mar 3. PMID: 38431835. DOI:10.1021/acs.jmedchem.3c02121
