- Design, synthesis and structure-activity-relationship of 1,5-tetrahydronaphthyridines as CETP inhibitors
-
This Letter describes the discovery and SAR optimization of 1,5-tetrahydronaphthyridines, a new class of potent CETP inhibitors. The effort led to the identification of 21b and 21d with in vitro human plasma CETP inhibitory activity in the nanomolar range (IC50 = 23 and 22 nM, respectively). Both 21b and 21d exhibited robust HDL-c increase in hCETP/hApoA1 dual heterozygous mice model.
- Fernandez, Maria-Carmen,Escribano, Ana,Mateo, Ana I.,Parthasarathy, Saravanan,Martin De La Nava, Eva M.,Wang, Xiaodong,Cockerham, Sandra L.,Beyer, Thomas P.,Schmidt, Robert J.,Cao, Guoqing,Zhang, Youyan,Jones, Timothy M.,Borel, Anthony,Sweetana, Stephanie A.,Cannady, Ellen A.,Stephenson, Gregory,Frank, Scott,Mantlo, Nathan B.
-
supporting information; scheme or table
p. 3056 - 3062
(2012/06/17)
-
- Pyrazinone Modulator of Corticotropin-Releasing Factor Receptor Activity
-
The invention relates to the compound (S)-4-(1-cyclopropyl-2-methoxyethyl)-6-(6-(difluoromethoxy)-2,5-dimethylpyridin-3-ylamino)-5-oxo-4,5-dihydropyrazine-2-carbonitrile, pharmaceutical compositions of the compound, and methods of using the compound for the treatment of psychiatric disorders and neurological diseases including depression, anxiety related disorders, irritable bowel syndrome, addiction and negative aspects of drug and alcohol withdrawal, and other conditions associated with CRF.
- -
-
Page/Page column 5; 14
(2010/03/02)
-
- 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 (CRF1) 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 CRF1 receptor antagonists and studies to assess the formation of reactive metabolites led to the discovery of 19e, a high affinity CRF1 receptor antagonist (IC50= 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. Anovel 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.,Ahuja, Vijay T.,Zhuo, Xiaoliang,Mattson, Ronald J.,Denhart, Derek J.,Deskus, Jeffrey A.,Vrudhula, Vivekananda M.,Pan, Senliang,Ditta, Jonathan L.,Shu, Yue-Zhong,Grace, James E.,Lentz, Kimberley A.,Lelas, Snjezana,Li, Yu-Wen,Molski, Thaddeus F.,Krishnananthan, Subramaniam,Wong, Henry,Qian-Cutrone, Jingfang,Schartman, Richard,Denton, Rex,Lodge, Nicholas J.,Zaczek, Robert,Macor, John E.,Bronson, Joanne J.
-
experimental part
p. 7653 - 7668
(2010/09/03)
-
- IMIDAZOPYRIDINE COMPOUND
-
A compound represented by the following general formula (1), or a salt or hydrate thereof: wherein R1 represents a C1-C6 alkyl group or C2-C6 alkynyl group which may be substituted, or a phenyl group which may be substituted, R2 represents a hydrogen atom or a C1-C6 alkyl group, R3 represents methyl or ethyl group, R4 represents a C1-C6 alkyl group, R5 represents a hydrogen atom, provided that a compound wherein R1 is a C1-C6 alkyl group unsubstituted or substituted with a halogen atom and R2 is a hydrogen atom is excluded.
- -
-
-