| Target Validation Information | |||||
|---|---|---|---|---|---|
| Target ID | T45262 | ||||
| Target Name | Corticotropin releasing factor receptor 1 | ||||
| Target Type | Successful |
||||
| Drug Potency against Target | N-mesityl-6-methyl-3-tosylpyridin-2-amine | Drug Info | Ki = 145 nM | [527873] | |
| N-mesityl-4,6-dimethyl-3-tosylpyridin-2-amine | Drug Info | Ki = 1778 nM | [527873] | ||
| CP-376395 | Drug Info | IC50 = 5.1 nM | [529324] | ||
| BMS-561388 | Drug Info | IC50 = 66 nM | [530071] | ||
| Pexacerfont | Drug Info | IC50 = 6.1 nM | [553027] | ||
| SR-125543A | Drug Info | Ki = 2 nM | [529622] | ||
| PD-171729 | Drug Info | Ki = 5 nM | [534796] | ||
| DMP-696 | Drug Info | IC50 = 1.2 nM | [530226] | ||
| Action against Disease Model | GSK561679 | NBI-77860/GSK561679 was identified as a high affinity ligand of CRF1 with a pK(i) value of 8.2 and a functional CRF(1) antagonist with pIC(50) value of 7.0 in the in vitro CRF ACTH production assay | [553080] | Drug Info | |
| The Effect of Target Knockout, Knockdown or Genetic Variations | As CRF(1)R-deficient mice have (+/+), CRF(1)R (+/-) and CRF(1)R (-/-) mice colonic sensitivity was assessed via a visceromotor behavioural response (VMR) induced by colorectal distension (CRD, 0-60 mmHg). In the CRF(1)R (+/+) mice there was a pressure-dependent increase in the VMR to CRD that was moderately attenuated in the CRF1R (+/-) mice. However in the CRF(1)R (-/-) mice a VMR to CRD was only observed at the highest distension pressure (60 mmHg). A CRF(1)R antagonist, NBI 30775 (30 mg kg(-1) i.p.) significantly decreased the VMR to CRD in CRF(1)R +/+ mice. An identical inhibitory effect of NBI 30775 was observed in 43% of the CRF(1)R +/- mice. This study provides pharmacological and genetic evidence for the importance of CRF(1)R in colonic sensitivity and suggests a link between stress and visceral perception | [553080] | |||
| References | |||||
| Ref 553080 | Discovery of NBI-77860/GSK561679, a potent corticotropin-releasing factor (CRF1) receptor antagonist with improved pharmacokinetic properties. Bioorg Med Chem Lett. 2010 Dec 15;20(24):7259-64. doi: 10.1016/j.bmcl.2010.10.095. Epub 2010 Oct 25. | ||||
| Ref 527873 | Bioorg Med Chem Lett. 2006 Feb 15;16(4):934-7. Epub 2005 Nov 16.Synthesis and evaluation of 2-anilino-3-phenylsulfonyl-6-methylpyridines as corticotropin-releasing factor1 receptor ligands. | ||||
| Ref 527873 | Bioorg Med Chem Lett. 2006 Feb 15;16(4):934-7. Epub 2005 Nov 16.Synthesis and evaluation of 2-anilino-3-phenylsulfonyl-6-methylpyridines as corticotropin-releasing factor1 receptor ligands. | ||||
| Ref 529324 | J Med Chem. 2008 Mar 13;51(5):1385-92. Epub 2008 Feb 21.2-aryloxy-4-alkylaminopyridines: discovery of novel corticotropin-releasing factor 1 antagonists. | ||||
| Ref 530071 | J Med Chem. 2009 May 14;52(9):3073-83.8-(4-Methoxyphenyl)pyrazolo[1,5-a]-1,3,5-triazines: selective and centrally active corticotropin-releasing factor receptor-1 (CRF1) antagonists. | ||||
| Ref 553027 | Progress in corticotropin-releasing factor-1 antagonist development. Drug Discov Today. 2010 May;15(9-10):371-83. doi: 10.1016/j.drudis.2010.02.011. Epub 2010 Mar 3. | ||||
| Ref 529622 | Bioorg Med Chem Lett. 2008 Aug 15;18(16):4486-90. Epub 2008 Jul 18.2-Arylpyrimidines: novel CRF-1 receptor antagonists. | ||||
| Ref 534796 | Bioorg Med Chem Lett. 1998 Aug 18;8(16):2067-70.Pyrazolo[1,5-a]pyrimidine CRF-1 receptor antagonists. | ||||
| Ref 530226 | J Med Chem. 2009 Jul 23;52(14):4161-72.In vitro intrinsic clearance-based optimization of N3-phenylpyrazinones as corticotropin-releasing factor-1 (CRF1) receptor antagonists. | ||||
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