The discovery of 4-(3-pentylamino)-2,7-dimethyl-8-(2-methyl-4-methoxyphenyl)-pyrazolo-[1,5- a ]-pyrimidine: A corticotropin-releasing factor (hCRF 1 ) antagonist

Gilligan, Paul J.; Baldauf, Caryn; Cocuzza, Anthony J.; Chidester, Dennis R.; Zaczek, Robert; Fitzgerald, Lawrence W.; Mcelroy, J; Smith, Mark A.; Shen, Helen; Saye, J; Christ, David D.; Trainor, George L.; Robertson, David W.; Hartig, Paul

doi:10.1016/s0968-0896(99)00271-0

Cited by 85 publications

(51 citation statements)

References 31 publications

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“…The effect on affinity of these upper aliphatic groups depended on their size, branching pattern and, where a chiral center was present, the stereochemical configuration (Gilligan et al, 2000a;Gross et al, 2005). We evaluated the kinetics underlying the affinity contribution of the upper aliphatic groups at the R3 position of the NBI 34041 scaffold (Fig.…”

Section: Min) B Nbi 35965 (16 Min) C Nbi 30775 (22 H) D Ssr125mentioning

confidence: 99%

Binding Kinetics Redefine the Antagonist Pharmacology of the Corticotropin-Releasing Factor Type 1 Receptor

Fleck¹,

Hoare²,

Pick³

et al. 2012

J Pharmacol Exp Ther

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Corticotropin-releasing factor (CRF) receptor antagonists are under preclinical and clinical investigation for stress-related disorders. In this study the impact of receptor-ligand binding kinetics on CRF 1 receptor antagonist pharmacology was investigated by measuring the association rate constant (k 1 ), dissociation rate constant (k Ϫ1 ), and kinetically derived affinity at 37°C. Three aspects of antagonist pharmacology were reevaluated: comparative binding activity of advanced compounds, in vivo efficacy, and structure-activity relationships. Twelve lead compounds, with little previously noted difference of affinity, varied substantially in their kinetic binding activity with a 510-fold range of kinetically derived affinity (k Ϫ1 /k 1 ), 170-fold range of k Ϫ1 , and 13-fold range of k 1 . The k Ϫ1 values indicated previous affinity measurements were not close to equilibrium, resulting in compression of the measured affinity range. Dissociation was exceptionally slow for three ligands (k Ϫ1 t 1/2 of 1.6 -7.2 h at 37°C). Differences of binding behavior were consistent with in vivo pharmacodynamics (suppression of adrenocorticotropin in adrenalectomized rats). Ligand concentration-effect relationships correlated with their kinetically derived affinity. Two ligands that dissociated slowly (53 and 130 min) produced prolonged suppression, whereas only transient suppression was observed with a more rapidly dissociating ligand (16 min). Investigating the structure-activity relationship indicated exceptionally low values of k 1 , approaching 100,000-fold less than the diffusion-limited rate. Retrospective interpretation of medicinal chemistry indicates optimizing specific elements of chemical structure overcame kinetic barriers in the association pathway, for example, constraint of the pendant aromatic orthogonal to the ligand core. Collectively, these findings demonstrate receptor binding kinetics provide new dimensions for understanding and potentially advancing the pharmacology of CRF 1 receptor antagonists.

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Section: Min) B Nbi 35965 (16 Min) C Nbi 30775 (22 H) D Ssr125mentioning

confidence: 99%

Binding Kinetics Redefine the Antagonist Pharmacology of the Corticotropin-Releasing Factor Type 1 Receptor

Fleck¹,

Hoare²,

Pick³

et al. 2012

J Pharmacol Exp Ther

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“…In addition, the same compound showed anxiolytic and antidepressant efficacy in a small, open-labeled clinical study (Zobel et al, 2000). Likewise, several other CRF 1 antagonists including CRA1000 and CRA1001 (Okuyama et al, 1999), DMP695 (Bakthavatchalam et al, 1998;Millan et al, 2001), DMP696 (McElroy et al, 2002), and DMP904 (Gilligan et al, 2000b;Takahashi et al, 2001) have shown anxiolytic profiles in preclinical animal models. For peripherally applied nonpeptide CRF 1 antagonists to be effective, these compounds should have good plasma drug exposure, blood-brain barrier penetration, and brain CRF 1 receptor occupancy.…”

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confidence: 92%

Receptor Occupancy of Nonpeptide Corticotropin-Releasing Factor 1 Antagonist DMP696: Correlation with Drug Exposure and Anxiolytic Efficacy

Li¹,

Hill²,

Wong³

et al. 2003

J Pharmacol Exp Ther

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4-(1,3-Dimethoxyprop-2-ylamine)-2,7-dimethyl-8-(2,4-dichlorophenyl)-pyrazolo[1,5-a]-1,3,5-triazine (DMP696) is a highly selective and potent, nonpeptide corticotropin-releasing factor 1 (CRF 1 ) antagonist. In this study, we measured in vivo CRF 1 receptor occupancy of DMP696 by using ex vivo ligand binding and quantitative autoradiography and explored the relationship of receptor occupancy with plasma and brain exposure and behavioral efficacy. In vitro affinity (IC 50 ) of DMP696 to brain CRF 1 receptors measured using the brain section binding autoradiography in this study is similar to that assessed using homogenized cell membrane assays previously. The ex vivo binding assay was validated by demonstrating that potential underestimation of receptor occupancy with this procedure could be minimized by identifying an appropriate in vitro incubation time (40 min) based upon the dissociation kinetics of DMP696. Orally administrated DMP696 dose dependently occupied CRF 1 receptors in the brain, with ϳ60% occupancy at 3 mg/kg. In the defensive withdrawal test of anxiety, this dose of DMP696 produced approximately 50% reduction in the exit latency. The time course of plasma and brain drug levels paralleled that of receptor occupancy, with peak exposure at 90 min after dosing. The plasma-free concentration of DMP696 corresponding to 50% CRF 1 receptor occupancy (in vivo IC 50 , 1.22 nM) was similar to the in vitro IC 50 (ϳ1.0 nM). Brain concentrations of DMP696 were over 150-fold higher than the plasma-free levels. In conclusion, doses of DMP696 occupying over 50% brain CRF 1 receptors are consistent with doses producing anxiolytic efficacy in the defense withdrawal test of anxiety, and the IC 50 value estimated in vivo based on plasmafree drug concentrations is consistent with the in vitro IC 50 value.Corticotropin releasing factor (CRF), a 41-amino acid peptide, plays a pivotal role in the behavioral, endocrine, immune, and autonomic responses of the body to stress (Owens and Nemeroff, 1991). In addition to the hypothalamic paraventricular nucleus where it was originally identified, CRF is also widely distributed across brain regions (Chalmers et al., 1996;Heinrichs and De Souza, 1999;Gilligan et al., 2000a). The physiological functions of CRF are mediated by at least two G-protein coupled receptors, CRF 1 and CRF 2 (including splice variants CRF 2␣ , CRF 2␤ , CRF 2␥ ), both of which are linked to adenylyl cyclase activation but have distinct brain distributions. CRF 1 receptors are widespread in the cortex, limbic system, cerebellum, and pituitary, whereas CRF 2 receptors are dominant in subcortical areas including the lateral septum (CRF 2␣ ), ventromedial hypothalamus (CRF 2␣ ), and choroid plexus (CRF 2␤ ) (De Souza, 1987;Chalmers et al., 1995;Primus et al., 1997;Rominger et al., 1998).Increasing evidence suggests that the CRF system is involved in pathophysiology of anxiety disorders (Heinrichs and De Souza, 1999;Gilligan et al., 2000a). Intracerebroventricular administration of CRF induces stress beha...

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“…New series of isoxazolines has been synthesized and has shown moderate antimicrobial activity 59 [70]. Pyrimidine analogues: N-fused analogues of chalcones particularly pyrimidines have received augmented interest due to their plethora of biological actions such as antifungal [71], antibacterial [72], antitumor [73], analgesics [74], anti-inflammatory [75], anti-trichomonal [76], KDR kinase inhibition [77], CRF-1 receptor antagonists [78,79] estrogen receptor ligands, and COX-2 selective inhibition [80]. Sharma et al synthesized a series of quinolinyl chalcones and quinolinyl pyrimidines and screened them against M. tuberculosis and NF-54 strains of P. falciparum among all compounds with 4-amino linkage showed promising activity against NF-54 strains of P. falciparum.…”

Section: Analogues Of Chalcones Pyrazoline Analogues With Various Phamentioning

confidence: 99%

Chalconoid Derived Heterocycles as Potent Bioactive Molecules: A Review

Sapra¹,

Sharma²

2016

Chem Sci J

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Although chalcones symbolize an important pharmacophore for variety of biological actions, however their analogues are also reported to be equally important for plethora of biological actions. In the present review, a comprehensive study of chalcones derived molecules (like pyrazoles, isoxazoles, pyridine, pyrimidine) their pharmacological actions, mechanism of action, structure activity relationship studies have been described. which includes anti-proliferative, anti-inflammatory, antioxidant, proapoptotic, anti-bacterial and anti-adhesive effects [18]. Analogues of chalcones Pyrazoline analogues with various pharmacological activities:Pyrazole nucleus present in compounds exhibit wide range of biological activity. Introduction of a pyrazole ring in the chalcones between the two aryl rings increase the cytotoxic activity against a series of human cancer cell lines. Dhar et al. [19] synthesized a series of 1-acetyl-3,5-diaryl-4,5-dihydro-(H)-pyrazoles and assayed for in vitro cytotoxicity against PC-3, OVCAR, IMR-32, HEP-2 human cancer cell lines, compound 1 showed broad spectrum cytotoxic activity against all the four cell lines. The activity shown by the compounds conclude that (i) Substitution on phenyl ring showed marked effect on cytotoxic activity, (ii) Presence of electron donating groups on phenyl ring led to enhanced activity whereas electron withdrawing group except NO 2 reduces the cytotoxic activity, (iii) Replacement of phenyl ring with heterocyclic ring also reduces the cytotoxic potential and napthyl ring on both sides are more beneficial for cytotoxic potential Chemical Sciences JournalChem ic a l S cience s J o u rnal

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The discovery of 4-(3-pentylamino)-2,7-dimethyl-8-(2-methyl-4-methoxyphenyl)-pyrazolo-[1,5- a ]-pyrimidine: A corticotropin-releasing factor (hCRF 1 ) antagonist

Cited by 85 publications

References 31 publications

Binding Kinetics Redefine the Antagonist Pharmacology of the Corticotropin-Releasing Factor Type 1 Receptor

Binding Kinetics Redefine the Antagonist Pharmacology of the Corticotropin-Releasing Factor Type 1 Receptor

Receptor Occupancy of Nonpeptide Corticotropin-Releasing Factor 1 Antagonist DMP696: Correlation with Drug Exposure and Anxiolytic Efficacy

Chalconoid Derived Heterocycles as Potent Bioactive Molecules: A Review

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