Table 1.
CRF1 receptor antagonists. This table summarizes current publically-available information about compounds reported to be (or presumed to be, if data are not available) non-peptidic, potent, selective, orally active antagonists of the CRF1 receptor. Numerous agents listed are not in development but are used as pharmacological probes in animal studies. Some agents have reached clinical testing in various disorders, as described by publications and/or company press releases, and some are reported to be discontinued. “CRF1 Aff.” refers to reported or estimated affinity in CRF1 receptor binding assays (IC50 or Ki, in nM). (n.a. = not available)
| Name | Company/ Stakeholder |
Chemical Name | CRF1 Aff. |
Status (estimated farthest advanced) |
References |
|---|---|---|---|---|---|
| Antalarmin | N-butyl-N-ethyl-2,5,6-trimethyl-7-(2,4,6- trimethylphenyl)pyrrolo[3,2-e]pyrimidin-4-amine |
<10 | Preclinical | (Seymour, Schmidt, & Schulz, 2003) | |
| CP-154,526 | Pfizer | (2,5-dimethyl-3-(6-dimethyl-4-methylpyridin-3-yl)- 7-dipropylamino-pyrazolo [1,5-a]pyrimidine) |
<10 | Preclinical | (Schulz, et al., 1996; Seymour, et al., 2003) |
| CP-316,311 | Pfizer | 3,6-dimethyl-4-(pentan-3-yloxy)-2-(2,4,6- trimethylphenoxy)pyridine |
<10 | Phase II, depression; double blind, placebo controlled;no difference vs placebo |
(Binneman, et al., 2008); www.bindingdb.org |
| CRA1000 | Taisho | 2-[N-(2-methylthio-4-isopropylphenyl)-N- ethylamino]-4-[4-(3-fluorophenyl)-1,2,3,6- tetrahydropyridin-1-yl)-6-methylpyrimidine |
20–40 | Preclinical | (Chaki, et al., 1999; Okuyama, et al., 1999) |
| CRA1001 | Taisho | 2-[N-(2-bromo-4-isopropylphenyl)-N-ethylamino]- 4-[4-(3-fluoropheny l)-1,2,3,6-tetrahydropyridin-1- yl)-6-methylpyrimidine |
20–40 | Preclinical | (Chaki, et al., 1999; Okuyama, et al., 1999) |
| CRA0450 | Taisho | 1-[8-(2,4-dichlorophenyl)-2-methylquinolin-4-yl]- 1,2,3,6-tetrahydropyridin e-4-carboxamide benzenesulfonate |
40–60 | Preclinical | (Chaki, et al., 2004; Dawe, et al., 2001) |
| DMP696 | BMS | 4-(1,3-Dimethoxyprop-2-ylamino)-2,7-dimethyl-8- (2, 4-dichlorophenyl)pyrazolo[1,5-a]-1,3,5-triazine |
<10 | Preclinical | (Li, et al., 2005) |
| DMP904 | BMS | [4-(3-pentylamino)-2,7-dimethyl-8-(2-methyl-4- methoxyphenyl)-pyrazolo-[1,5 -a]-pyrimidine] |
n.a. | Preclinical | (Li, et al., 2005) |
| GSK561679 | GSK/ Neurocrine |
n.a. | n.a. | Phase II, depression; double blind, placebo controlled; registered 08/08; completed but results not published |
www.clinicaltrials.gov |
| Phase I, social anxiety disorder; registered 11/07; double blind; completed but results not published |
www.clinicaltrials.gov | ||||
| Phase II, PTSD, females;double blind, placebo controlled; registered 11/09 |
www.clinicaltrials.gov | ||||
| Experimental, human startle, females; registered |
www.clinicaltrials.gov | ||||
| Experimental, emotional processing (fMRI); double blind; registered 8/07; completed but results not published |
www.clinicaltrials.gov | ||||
| GSK586529 | GSK/ Neurocrine |
n.a. | n.a. | Phase I, depression | www.clinicaltrials.gov |
| GW876008 | GSK/ Neurocrine |
n.a. | n.a. | Phase II, social anxiety disorder; double blind, placebo controlled; no difference vs placebo |
www.clinicaltrials.gov |
| Phase II, IBS; double blind, placebo controlled; completed; results not published |
www.clinicaltrials.gov ; www.neurocrine.com | ||||
| Phase I, emotional processing (fMRI); registered 1/07; completed but results not published |
www.clinicaltrials.gov | ||||
| MJL-1-109-2 | pyrazolo[1,5-a]-1,3,5-triazin-4-amine,8-[4- (bromo)-2-chlorophenyl]-N, N-bis(2- methoxyethyl)-2,7-dimethyl-(9Cl) |
<10 | Preclinical | (Zhao, et al., 2007) | |
| MPZP | Salk Institute | N,N-bis(2-methoxyethyl)-3-(4-methoxy-2- methylphenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-amine |
<10 | Preclinical | (Richardson, et al., 2008) |
| MTIP | NIAAA/Eli Lilly |
3-(4-Chloro-2-morpholin-4-yl-thiazol-5-yl)-8-(1- ethylpropyl)-2,6-dimethyl-imidazo[1,2- b]pyridazine |
<10 | Preclinical | (Gehlert, et al., 2007) |
| NBI3b1996 | Neurocrine | (N-Cyclopropylmethyl-2,5-dimethyl-N-propyl-N'- (2,4,6-trichloro-phenyl)-pyr imidine-4,6-diamine) |
<10 | Preclinical | (Gehlert, et al., 2005) |
| NBI-34041 | GSK/Neuroc rine |
2-(2,4-dichlorophenyl)-4-methyl-6-(1-propylbutyl)- 7,8-dihydro-6H-1,3,6,8a-tetraazaacenaphthylene |
<10 | Reduced stress-induced ACTH release and corticosterone in Trier Social Stress Test |
(Ising, et al., 2007) |
| ONO-2333Ms | Ono | n.a. | n.a. | Program discontinued due to lack of efficacy (07/08) |
www.clinicaltrials.gov |
| Pexacerfont (BMS-562086) | BMS | 8-(6-methoxy-2-methylpyridin-3-yl)-2,7-dimethyl- N-[(1R)-1-methylpropyl]pyrazolo[1,5-a]-1,3,5- triazin-4-amine |
n.a. | Phase II, depression; listed as completed 10/07; results conveyed as personal communication from V. Coric, M.D. |
www.clinicaltrials.gov; |
| Phase II, GAD | (Coric, et al., 2010) | ||||
| Phase II, IBS; listed as completed 01/08 but results not published |
www.clinicaltrials.gov | ||||
| PF-572778 | Pfizer | n.a. | n.a. | ||
| R121919 (NBI27914) | GSK/Neuroc rine |
(2,5-dimethyl-3-(6-dimethyl-4-methylpyridin-3-yl)- 7-dipropylamino-pyrazolo [1,5-a]pyrimidine) |
<10 | Phase II (open-label; depression); active; discontinued due to abnormal liver function tests |
(Chen, et al., 1996; Saunders & Williams, 2001) |
| R27899 (CRA0450) | Taisho/Johns on & Johson |
1-[8-(2,4-dichlorophenyl)-2-methylquinolin-4-yl]- 1,2,3,6-tetrahydropyridin e-4-carboxamide benzenesulfonate |
50–60 | Preclinical | (Chaki, et al., 2004) |
| R317573 | Taisho/Johns on & Johnson |
46 | Phase IIa; double-blind, placebo controlled; regional cerebral glucose metabolism PET study |
(Schmidt, et al., 2010) | |
| Phase IIa; double-blind, randomized, placebo- controlled |
(Dawson, et al., 2009) | ||||
| SSR125543 | Sanofi- Aventis |
4-(2-Chloro-4-methoxy-5-methylphenyl)-N-[(1S)- 2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]5- methyl-N-(2-propynyl)-1,3-thiazol-2-amine hydrochloride |
<10 | Preclinical | (Gully, et al., 2002) |