Design and Synthesis of a Series of Non-Peptide High-Affinity Human Corticotropin-Releasing Factor<sub>1</sub> Receptor Antagonists

Chen, C.; Dagnino, Raymond; Souza, Errol B. De; Grigoriadis, Dimitri E.; Huang, Charles Q.; Kim, K.-I.; Liu, Z.; Moran, Terry; Webb, Thomas R.; Whitten, Jeffrey P.; Xie, Yuanyang; McCarthy, James R.

doi:10.1021/jm960149e

Cited by 149 publications

(63 citation statements)

References 12 publications

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“…[6,9] The progression from then was slow until 1996, [61][62][63] [6,61,62, Although biological activity is prominent, with many sub-nanomolar derivatives available, substantial problems prevail and include poor bioavailability, toxicity, lack of structural diversity, and potentially low specificity (high receptor distribution) and thus high possibility of side effects. [16,85] Solubility is a considerable issue with CRH non-peptide antagonists.…”

Section: Antagonists Drug Design For Crhmentioning

confidence: 99%

Corticotropin Releasing Hormone - A GPCR Drug Target

Hemley

McCluskey²,

Keller³

2007

CDT

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Corticotrophin Releasing Hormone (CRH) is a primary hormone in the fight or flight response targeting a membrane bound G-protein coupled receptor (GPCR). Many people worldwide stand to benefit by the development of CRH agonists and antagonists for the treatment of anxiety and depression, with additional therapeutic targets including Alzheimer's, pain and the prevention of premature birth: so why the delay in development? In this review, we will discuss not only CRH, related proteins, receptors and ligands, but some of the obstacles that have arisen, as well as strategies being pursued to overcome these problems in the pursuit of this GPCR targeted therapeutic. Several key proteins influence the complex and intrinsic regulation of CRH, including its receptors (CRHR), of which 3 types have been categorised, CRHR1, CRHR2, CRHR3, each containing active and inactive splice variants. Additionally, the CRH binding protein (CRHBP) is believed to moderate the effects of CRH at the receptor, whether it is as a molecular mop, or a delivery vessel, or both, is still being investigated. Homology based receptor modelling is a technique that has only recently become available with the crystallisation of bovine rhodopsin (a GPCR), [1] and the application of this technique to the CRH receptors is still in the early stages of development. Therefore, the medicinal chemist has previously had to rely on ligand-based strategies, specifically, the development of pharmacophores. Thus, an extensive number of both CRH peptide analogues and small ligands that show nanomolar antagonism have been developed with SAR libraries being integral to the iterative drug design process. Alzheimer's, pain and the prevention of premature birth: so why the delay in development? In this review, we will discuss not only CRH, related proteins, receptors and ligands, but some of the obstacles that have arisen, as well as strategies being pursued to overcome these problems in the pursuit of this GPCR targeted therapeutic.Several key proteins influence the complex and intrinsic regulation of CRH, including its receptors (CRHR), of which 3 types have been categorised, CRHR 1 , CRHR 2 , CRHR 3, each containing active and inactive splice variants. Additionally, the CRH binding protein (CRHBP) is believed to moderate the effects of CRH at the receptor, whether it is as a molecular mop, or a delivery vessel, or both, is still being investigated.Homology based receptor modelling is a technique that has only recently become available with the crystallisation of bovine rhodopsin (a GPCR), [1] and the application of this technique to the CRH receptors is still in the early stages of development. Therefore, the medicinal chemist has previously had to rely on ligand-based strategies, specifically, the development of pharmacophores. Thus, an extensive number of both CRH peptide analogues and small ligands that show nanomolar antagonism have been developed with SAR libraries being integral to the iterative drug design process.

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Section: Antagonists Drug Design For Crhmentioning

confidence: 99%

Corticotropin Releasing Hormone - A GPCR Drug Target

Hemley

McCluskey²,

Keller³

2007

CDT

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“…IUPAC rules are used for nomenclature of peptides including one-letter codes for amino acids. The following abbreviations are also used: Ac, acetyl; ACTH, adrenocorticotropin hormone; astressin, cyclo (30)(31)(32)(33)[DPhe 12 ,Nle 21,38 ,Glu 30 ,Lys 33 ]hCRF ; Boc, tertbutyloxycarbonyl; BOP, benzotriazolyloxy-tris(dimethylamino)phosphonium hexafluorophosphate; BSA, bovine serum albumin; CRF, corticotropin releasing factor (o ) ovine, h ) human); CRFR, CRF receptor; CZE, capillary zone electrophoresis; DCM, dichloromethane; DIC, diisopropylcarbodiimide; DMF, dimethylformamide; Fmoc, 9-fluorenylmethoxycarbonyl; HBTU, O-(benzotriazol- 1-yl inhibition of digestive functions (upper gastrointestinal tract), and activation of the lower gastrointestinal tract (elimination). 29 After intracerebroventricular administration of low doses, CRF stimulates arousal and increases performance in various learning and memory tests.…”

Section: Introductionmentioning

confidence: 99%

“…Such non-peptide ligands for CRF-R 1 have been described. [30][31][32][33][34][35][36][37] The fact that they cross the BBB, however, limits their use as investigative tools to dissect the role of CRF in either the CNS or the periphery, as they will be distributed in both compartments.…”

Section: Introductionmentioning

confidence: 99%

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Constrained Corticotropin Releasing Factor Antagonists (Astressin Analogues) with Long Duration of Action in the Rat

et al. 1999

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In an earlier report we identified specific modifications and substitutions of corticotropin releasing factor (CRF) that led to the discovery of antagonists with extended duration of action as compared to that of astressin {cyclo (30)(31)(32)(33) , which was found to be longer acting than astressin (Rivier, J.; et al. J. Med. Chem. 1998, 41, 5012-5019). To further increase the efficiency (potency, duration of action, and bioavailability) of this family of antagonists, we introduced two or more CRMe-leucine residues at positions shown in earlier studies to be favorable (Hernandez, J.-F.; et al.

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“…In a series of nonpeptide corticotropin-releasing factor 1 (CRF1) antagonists, scientists from Neurocrine [16] observed a dramatic change in affinity simply by shifting one nitrogen atom of the pyrimidine ring ( Fig. 1.7).…”

Section: Positional Isomers Produced As Analoguesmentioning

confidence: 99%

Analogues as a Means of Discovering New Drugs

Wermuth¹

2006

Analogue‐based Drug Discovery

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Design and Synthesis of a Series of Non-Peptide High-Affinity Human Corticotropin-Releasing Factor₁ Receptor Antagonists

Cited by 149 publications

References 12 publications

Corticotropin Releasing Hormone - A GPCR Drug Target

Corticotropin Releasing Hormone - A GPCR Drug Target

Constrained Corticotropin Releasing Factor Antagonists (Astressin Analogues) with Long Duration of Action in the Rat

Analogues as a Means of Discovering New Drugs

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Design and Synthesis of a Series of Non-Peptide High-Affinity Human Corticotropin-Releasing Factor1 Receptor Antagonists

Cited by 149 publications

References 12 publications

Corticotropin Releasing Hormone - A GPCR Drug Target

Corticotropin Releasing Hormone - A GPCR Drug Target

Constrained Corticotropin Releasing Factor Antagonists (Astressin Analogues) with Long Duration of Action in the Rat

Analogues as a Means of Discovering New Drugs

Contact Info

Product

Resources

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Design and Synthesis of a Series of Non-Peptide High-Affinity Human Corticotropin-Releasing Factor₁ Receptor Antagonists