Discovery of sodium R-(+)-4-{2-[5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-[trifluoromethyl]benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenylethylamino}butyrate (elagolix), a potent and orally available nonpeptide antagonist of the human gonadotropin-releasing hormone receptor.

The discovery of novel uracil phenylethylamines bearing a butyric acid as potent human gonadotropin-releasing hormone receptor (hGnRH-R) antagonists is described. A major focus of this optimization was to improve the CYP3A4 inhibition liability of these uracils while maintaining their GnRH-R potency. R-4-{2-[5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-[trifluoromethyl]benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenylethylamino}butyric acid sodium salt, 10b (elagolix), was identified as a potent and selective hGnRH-R antagonist. Oral administration of 10b suppressed luteinizing hormone in castrated macaques. These efforts led to the identification of 10b as a clinical compound for the treatment of endometriosis.

Zwitterionic uracil derivatives as potent GnRH receptor antagonists with improved pharmaceutical properties.

A novel series of potent zwitterionic uracil GnRH antagonists were discovered that showed reduced liability for CYP3A4 enzyme inhibition.

Potent and orally bioavailable zwitterion GnRH antagonists with low CYP3A4 inhibitory activity.

Incorporation of a carboxylic acid into a series of uracil derivatives as hGnRH-R antagonists resulted in a significant reduction of CYP3A4 inhibitory activity. Highly potent hGnRH antagonists with low CYP3A4 inhibitory liability, such as 8a and 8d, were identified. Thus, 8a had a K(i) of 2.2 nM at GnRH-R and an IC(50) of 36 microM at CYP3A4.

Humphrey Matrix perimetry in optic nerve and chiasmal disorders: comparison with Humphrey SITA standard 24-2.

PURPOSE: To compare the Humphrey Matrix 24-2 perimetry (Matrix; Carl Zeiss Meditec, Inc., Dublin, CA) with the standard automated perimetry Humphrey Visual Field Analyzer using SITA (Swedish Interactive Threshold Algorithm) program 24-2 (SAP; Carl Zeiss Meditec, Inc.) in neuro-ophthalmic disorders affecting the optic nerve and chiasm. METHODS: Matrix and SAP were performed on 93 patients with neuro-ophthalmic disorders affecting the optic nerve and optic chiasm. Three readers compared the total and pattern deviation probability plots and judged the similarity and the extent of the visual field defects. The sensitivity and specificity of both perimeters were calculated. RESULTS: Concordance was good in 61%, fair in 30%, and poor in 9% of the total deviation plots. For the pattern deviation, concordance was good in 52%, fair in 34%, and poor in 14%. The extent of field loss was equal in 50%, 23% more extensive with Matrix, and 27% more extensive with SAP for total deviation plots. For the pattern deviation, the extent was equal in 47%, 20% more extensive with Matrix and 33% more extensive with SAP. The sensitivity for detecting defects was 84% (SAP) and 77% (Matrix) for total deviation and 80% (SAP) and 79% (Matrix) for pattern deviation (no significant difference, P > 0.05). The specificity was 84% (SAP) and 86% (Matrix) for total deviation and 68% (SAP) and 74% (Matrix) for pattern deviation (no significant difference, P > 0.05). CONCLUSIONS: The new Humphrey Matrix 24-2 testing strategy provides a visual field testing method for optic nerve and chiasmal disorders that has fair to good concordance with the Humphrey SITA Standard 24-2 program. Both tests have similar sensitivity and specificity.

Sensitivity and specificity of the Humphrey Matrix to detect homonymous hemianopias.

PURPOSE: To compare the sensitivity and specificity of the Humphrey Matrix frequency-doubling perimeter (Carl Zeiss Meditec, Inc., Dublin, CA) to that of standard automated perimetry (SAP) in detecting homonymous hemianopic visual field defects. METHODS: Thirty-three patients with homonymous hemianopias and 50 normal subjects were tested with SAP with the Humphrey Visual Field Analyzer (SITA standard program 24-2) and Humphrey Matrix frequency-doubling perimetry, program 24-2 (Matrix) on the same day. Patients with hemianopias had lesions of the retrochiasmal visual system that were documented by magnetic resonance imaging or by computed tomography. To be classified as a hemianopic visual field defect, the abnormal test location had to be homonymous, respect the vertical meridian, and have no additional scattered abnormal points that obscured the hemianopic pattern. The sensitivity and specificity of SAP and Matrix in detecting hemianopic defects were calculated. The chi(2) test was used to test for differences between groups. RESULTS: The sensitivity for hemianopic defects by total deviation probability plots was 75% for SAP and 59% for Matrix (not statistically significant, P = 0.29). The sensitivity of hemianopic defects by pattern deviation probability plots was 88% for SAP and 69% for Matrix (not statistically significant, P = 0.13). The specificity of total deviation probability plots was 84% for SAP and 86% for Matrix. The specificity of the pattern deviation probability plots was 68% for SAP and 74% for Matrix. CONCLUSIONS: Although there was no statistically significant difference between the Matrix and SAP in the detection of hemianopias, the sensitivity of SAP was higher, probably because of the obscuration of defects by scattered abnormal test locations with the Matrix.

Identification of 2-(4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-3-yl)-ethylamine derivatives as novel GnRH receptor antagonists.

A novel series of 2-(4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-3-yl)-ethylamine derivatives were designed and synthesized as GnRH receptor antagonists. SAR studies led to a series of highly active molecules against both the rat and human receptors. Furthermore, one potent compound, 17j, demonstrated dose-dependent LH suppression in castrated rats.

Design and synthesis of tricyclic corticotropin-releasing factor-1 antagonists.

Antagonists of the corticotropin-releasing factor (CRF) neuropeptide should prove to be effective in treating stress and anxiety-related disorders. In an effort to identify antagonists with improved physicochemical properties, new tricyclic CRF(1) antagonists were designed, synthesized, and tested for biological activity. As a result of studies aimed at establishing a relationship between structure and CRF(1) binding affinity, NBI 35965 (12a) was identified as a high-affinity antagonist with a pK(i) value of 8.5. Compound 12a proved to be a functional CRF(1) antagonist with pIC(50) values of 7.1 and 6.9 in the in vitro CRF-stimulated cAMP accumulation and ACTH production assays, respectively, and 12a also reduced CRF or stress induced ACTH production in vivo.

1-(4-Amino-phenyl)-pyrrolidin-3-yl-amine and 6-(3-amino-pyrrolidin-1-yl)-pyridin-3-yl-amine derivatives as melanin-concentrating hormone receptor-1 antagonists.

Derivatives of 1-(4-amino-phenyl)-pyrrolidin-3-yl-amine and 6-(3-amino-pyrrolidin-1-yl)-pyridin-3-yl-amine were identified as potent and functionally active MCH-R1 antagonists. One compound with Ki = 2.3 nM demonstrated good oral bioavailability (32%) and in vivo efficacy in rats.

Uracils as potent antagonists of the human gonadotropin-releasing hormone receptor without atropisomers.

Uracil derivatives were designed and synthesized to avoid atropisomers observed in the 6-methyluracils as antagonists of the human GnRH receptor. Optimization at the 1- and 5-positions of the uracil resulted in potent compounds such as 24 (Ki=0.45 nM).

Design of 2,5-dimethyl-3-(6-dimethyl-4-methylpyridin-3-yl)-7-dipropylaminopyrazolo[1,5-a]pyrimidine (NBI 30775/R121919) and structure--activity relationships of a series of potent and orally active corticotropin-releasing factor receptor antagonists.

We have previously shown that 3-phenylpyrazolo[1,5-a]pyrimidines exemplified by 8 were potent antagonists of the human corticotropin-releasing factor-1 receptor. A series of 3-pyridylpyrazolo[1,5-a]pyrimidines 15, 25-30, 34, and 35 containing a weakly basic pyridine ring at the 3-position of the bicyclic nucleus was designed to reduce lipophilicity from the initial leads such as 7. Here, we showed that these 3-pyridyl compounds exhibited potent antagonists at the human CRF(1) receptor. Moreover, the hydrophilic and weakly basic pyridine moiety increased the water solubility of some analogues. Compound 26 h exhibited good binding affinity at the human CRF(1) receptor with a K(i) value of 3.5 nM. As a functional antagonist, it dose-dependently inhibited CRF-stimulated cAMP production in cells expressing the CRF(1) receptor (IC(50) = 50 nM), and CRF-stimulated ACTH release from cultured rat pituitary cells (IC(50) = 20 nM). 26 h had a log P value of 4.9 and water solubility of greater than 10 mg/mL. Pharmacokinetic studies in rats showed that 26 h was orally bioavailable and able to penetrate into the brain. 26 h has been demonstrated in vivo efficacy in animal behavioral models that measure anxiolytic activity. These results suggest that analogues from this series were potent CRF(1) receptor antagonists with proper physicochemical properties and good pharmacokinetic profiles. 26 h was developed into a clinical compound and exhibited efficacy in patients with major depression.

Synthesis of benzoylpyrimidines as antagonists of the corticotropin-releasing factor-1 receptor.

A series of benzoylpyrimidines derived from the anilinepyrimidine CRF(1) antagonists were synthesized. Several synthetic routes were developed to explore the SAR of this series of compounds. Compounds such as 8d (K(i) = 15 nM) exhibited high binding affinities at the human CRF(1) receptor.

Design and synthesis of 3-(2-pyridyl)pyrazolo[1,5-a]pyrimidines as potent CRF1 receptor antagonists.

A series of 3-(2-pyridyl)pyrazolo[1,5-a]pyrimidines was designed and synthesized as antagonists for the corticotrophin-releasing factor-1 (CRF(1)) receptor. Several compounds such as 20c (K(i)=10 nM) exhibited good binding affinities at the CRF(1) receptor. In addition, 20c had adequate solubility in water.

Optimization of 3-phenylpyrazolo[1,5-a]pyrimidines as potent corticotropin-releasing factor-1 antagonists with adequate lipophilicity and water solubility.

In our efforts to identify potent CRF(1) antagonists with proper physicochemical properties, a series of 3-phenylpyrazolo[1,5-a]pyrimidines bearing polar groups, such as amino, hydroxyl, methoxy, sulfoxide, were designed and synthesized. Several positions of the core structure were identified, where a polar group was tolerated with slight reduction in receptor binding. NBI 30545 (18n) was found to have good binding affinity and potent antagonistic activity at the human CRF(1) receptor. Moreover, this compound had proper lipophilicity (log D = 2.78) and good solubility in water (>10mg/mL), and exhibited good plasma and brain exposure when given orally.

Design, synthesis, and SAR of 2-dialkylamino-4-arylpyrimidines as potent and selective corticotropin-releasing factor(1) (CRF(1)) receptor antagonists.

A series of 2-dialkylamino-4-phenylpyrimidines (7) was designed and synthesized as CRF(1) antagonists. SAR studies of this series resulted in the discovery of potent and selective antagonists 7b and 7n bearing a 4-(2,4,6-trisubstituted-phenyl) ring and a bulky 2-(N-bis(cyclopropane)methyl-N-propyl)amino group.

Pretransplantation soluble adhesion molecule expression predicts outcome after living donor renal transplantation.

HYPOTHESIS: Occult pretransplantation systemic inflammation will identify patients at risk for poor outcomes after renal transplantation. DESIGN: Retrospective cohort study. Adhesion molecule levels were measured in pretransplantation serum samples from 86 recipients. Univariate and multivariate analyses were conducted to assess a possible correlation between serum adhesion molecule level and outcome. SETTING: University referral center. MAIN OUTCOME MEASURES: Allograft rejection and survival. RESULTS: Patients with low levels of vascular cell adhesion molecule 1 had less graft rejection (P=.007). Low levels of vascular cell adhesion molecule 1 independently predicted decreased rejection (relative risk, 0.17; P=.01), and high levels of vascular cell adhesion molecule 1 independently predicted graft loss (relative risk, 3.83; P=.02). Similar correlations were observed for intercellular adhesion molecule 1. CONCLUSIONS: Decreased pretransplantation adhesion molecule expression correlates with less rejection, and increased levels correlate with graft loss. Assessment of pretransplantation inflammatory status may be useful in optimizing immunosuppression therapy.

Synthesis of 3-phenylpyrazolo[4,3-b]pyridines via a convenient synthesis of 4-amino-3-arylpyrazoles and SAR of corticotropin-releasing factor receptor type-1 antagonists.

3-Phenylpyrazolo[4,3-b]pyridines were synthesized via a cyclization of 4-amino-3-phenylpyrazoles 11-13 with ethyl acetoacetate. These compounds were found to be potent CRF(1) antagonists. The 2-alkylpyrazolo[4,3-b]pyridines were more polar but less active than the corresponding 1-alkyl-isomers.

Synthesis of 1-methyl-3-phenylpyrazolo[4,3-b]pyridines via a methylation of 4-phthalimino-3-phenylpyrazoles and optimization toward highly potent corticotropin-releasing factor type-1 antagonists.

1-Methyl-3-phenylpyrazolo[4,3-b]pyridines were synthesized via a cyclization reaction of 1-methyl-4-amino-3-phenylpyrazoles 8 with ethyl acetoacetate. Optimization of this series of compounds resulted in CRF(1) antagonists with subnanomolar binding affinity. Compounds bearing a polar group such as methoxy or hydroxy were also found to be very active.

Synthesis and SAR of 8-arylquinolines as potent corticotropin-releasing factor1 (CRF1) receptor antagonists.

A series of 4-substituted 8-aryl-2-methylquinolines 4 was designed and synthesized as highly potent antagonists for the human CRF(1) receptor. This series of compounds displayed parallel SAR to other bicyclic systems such as pyrazolo[1,5-a]pyrimidines, with several compounds possessing low nanomolar binding affinity. In addition to the high potency, the basicity of this 4-aminoquinoline core may offer CRF(1) antagonists with lower lipophilicity.

6,7-dihydroxyisoquinoline-3-carboxylic acids are potent inhibitors on the binding of insulin-like growth factor (IGF) to IGF-binding proteins: optimization of the 1-position benzoyl side chain.

A series of 1-benzoyl isoquinolines, based on compound 1, was synthesized and evaluated for their ability to displace IGF-I from its complex with IGF-binding protein-3. Successful modifications of 1 included the replacement of the 3,4-dihydroxybenzoyl group with a substituted benzyl group. These alternations culminated in the discovery of compounds such as 7o which had excellent in vitro potency (K(i)=9.4 nM) but with one less of the labile catechol functionality of 1.

Aniridia and Brachmann-de Lange syndrome: a review of ocular surface and anterior segment findings.

PURPOSE: To review the ocular surface and anterior segment findings in Brachmann-de Lange syndrome and describe a new case involving aniridia and congenital glaucoma. METHODS: A newborn presented 2 days after birth with bilateral cloudy corneas, photophobia, and epiphora. We provide a 5-year descriptive history and clinical course with review of the literature on Brachmann-de Lange syndrome. RESULTS: Multiple ocular surgeries were performed for ocular sequelae from aniridia and congenital glaucoma including Ahmed valve placement and penetrating keratoplasties in both eyes. At 5.5 years of age, the child had a clear graft OD and amblyopia from graft failure OS following recurrent graft infections. A review of Brachmann-de Lange syndrome found 43 patients with ocular surface and anterior segment findings. The most common findings included conjunctivitis, blepharitis, microcornea, and corectopia. Aniridia and congenital glaucoma were not previously reported with Brachmann-de Lange syndrome. CONCLUSIONS: Ocular surface and anterior segment abnormalities must be considered when examining patients with Brachmann-de Lange syndrome. Ocular findings may include vision-threatening anomalies, as in our case with aniridia and congenital glaucoma. To our knowledge, these findings are previously unreported in Brachmann-de Lange syndrome.