A strategy to minimize reactive metabolite formation: discovery of (S)-4-(1-cyclopropyl-2-methoxyethyl)-6-[6-(difluoromethoxy)-2,5-dimethylpyridin-3-ylamino]-5-oxo-4,5-dihydropyrazine-2-carbonitrile as a potent, orally bioavailable corticotropin-releasing factor-1 receptor antagonist.
Detailed metabolic characterization of 8, an earlier lead pyrazinone-based corticotropin-releasing factor-1 (CRF(1)) receptor antagonist, revealed that this compound formed significant levels of reactive metabolites, as measured by in vivo and in vitro biotransformation studies. This was of particular concern due to the body of evidence suggesting that reactive metabolites may be involved in idiosyncratic drug reactions. Further optimization of the structure-activity relationships and in vivo properties of pyrazinone-based CRF(1) receptor antagonists and studies to assess the formation of reactive metabolites led to the discovery of 19e, a high affinity CRF(1) receptor antagonist (IC(50) = 0.86 nM) wherein GSH adducts were estimated to be only 0.1% of the total amount of drug-related material excreted through bile and urine, indicating low levels of reactive metabolite formation in vivo. A novel 6-(difluoromethoxy)-2,5-dimethylpyridin-3-amine group in 19e contributed to the potency and improved in vivo properties of this compound and related analogues. 19e had excellent pharmacokinetic properties in rats and dogs and showed efficacy in the defensive withdrawal model of anxiety in rats. The lowest efficacious dose was 1.8 mg/kg. The results of a two-week rat safety study with 19e indicated that this compound was well-tolerated.
Hartz
Richard A
RA
Neuroscience Discovery Chemistry, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, Connecticut 06492, USA.
Ahuja
Vijay T
VT
Zhuo
Xiaoliang
X
Mattson
Ronald J
RJ
Denhart
Derek J
DJ
Deskus
Jeffrey A
JA
Vrudhula
Vivekananda M
VM
Pan
Senliang
S
Ditta
Jonathan L
JL
Shu
Yue-Zhong
YZ
Grace
James E
JE
Lentz
Kimberley A
KA
Lelas
Snjezana
S
Li
Yu-Wen
YW
Molski
Thaddeus F
TF
Krishnananthan
Subramaniam
S
Wong
Henry
H
Qian-Cutrone
Jingfang
J
Schartman
Richard
R
Denton
Rex
R
Lodge
Nicholas J
NJ
Zaczek
Robert
R
Macor
John E
JE
Bronson
Joanne J
JJ
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D004285:Dogs; D055808:Drug Discovery; D004355:Drug Stability; D006801:Humans; D008297:Male; D011719:Pyrazines / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology*; D011725:Pyridines / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors*; D000099052:CRF Receptor, Type 1
C545997:4-(1-cyclopropyl-2-methoxyethyl)-6-(6-(difluoromethoxy)-2,5-dimethylpyridin-3-ylamino)-5-oxo-4,5-dihydropyrazine-2-carbonitrile; D011719:Pyrazines; D011725:Pyridines; D018019:Receptors, Corticotropin-Releasing Hormone; D000099052:CRF Receptor, Type 1