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Adrenocorticotropic hormone analogs and related methods

An analog, adrenal membrane technology, applied in adrenocorticotropic hormone, chemical instruments and methods, drug combinations, etc., can solve the problems of impaired immune function, decreased growth, excessive production of adrenal stress hormones, etc.

Inactive Publication Date: 2008-05-28
UNIVERSITY OF DENVER +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In mammals, poultry, and fish, however, this often results in overproduction of adrenal stress hormones, which can have deleterious consequences, including impaired immune function and reduced growth

Method used

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  • Adrenocorticotropic hormone analogs and related methods
  • Adrenocorticotropic hormone analogs and related methods
  • Adrenocorticotropic hormone analogs and related methods

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0194] Example 1 Serum corticosteroid induction assay (in vivo)

[0195] ACTH analogs having reduced ACTH-mediated corticosteroid secretion are identified by performing an in vivo serum corticosteroid induction assay to measure corticosteroid levels in the subject's blood following administration of the ACTH analog.

[0196] In vivo serum corticosteroid induction assays were performed according to the following method. First, dexamethasone (0.4mg / 0.1ml PBS per mouse; Sigma, St.Louis, MO ) to inhibit their endogenous ACTH production. See Hajos, GT et al., "Studies of the potency of polypeptides with ACTH action by a new method based on continuous measurement of plasma corticosterone," Steroids Lipids Res 3:225-228 (1972); Costa, JL et al., "Mutational analysis of evolutionarily conserved ACTH residues, "GenComp Endocrinol, 136:12-16 (2004); and Karpac, J et al., "Development, Maintenance, and Function of the Adrenal Gland in Early Postnatal Pro-opiomelanocortin Null Mutant Mi...

Embodiment 2

[0199] Example 2 Serum corticosteroid inhibition assay (in vivo)

[0200] ACTH analogs with reduced ACTH-mediated corticosteroid secretion were identified by testing their ability to inhibit adrenal hormone production induced by unmodified ACTH by performing an in vivo serum corticosteroid inhibition assay. Corticosteroid levels in the blood of a subject are measured following administration of an ACTH analog test compound in combination with a compound having known corticosteroid-inducing activity (eg, ACTH or another ACTH analog). The ACTH analog test compound can be administered before, simultaneously with, or after the administration of the corticosteroid-producing compound.

[0201] In vivo serum corticosteroid suppression assays were performed as follows. ACTH analog test compounds, such as those in Table 1 with low activity, were tested for their ability to inhibit adrenal hormone production induced by unmodified ACTH.

[0202] First, dexamethasone (0.4mg / 0.1ml PBS pe...

Embodiment 3

[0206] Example 3 Adrenal binding assay (in vitro)

[0207] ACTH analogs with the ability to bind adrenal receptors can be identified by performing an in vitro adrenal binding assay. The amount of radiolabeled ACTH analog test compound bound to explanted adrenal membranes can be determined to identify ACTH analogs with adrenal receptor binding activity. Preferably, this is performed in serum-free medium (in vitro serum-free adrenal binding assay).

[0208] In vitro adrenal competitive binding assays can also identify ACTH analogs that have the ability to bind adrenal receptors with a higher binding affinity than compounds known to have adrenal binding activity (preferably ACTH), In the in vitro adrenal gland competitive binding assay, the reduction in the amount of radiolabeled compound that binds to the adrenal gland (such as ACTH) is measured by measuring the non-radiolabeled ACTH analog test compound in the medium containing explanted adrenal gland membranes. Different conce...

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PUM

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Abstract

ACTH analog compounds of the present invention include compounds comprising an ACTH peptide sequence with one or more structural modifications that can have one or more of the following preferred ACTH analog biological functions: (1) reduction of corticosteroid secretion by adrenal membrane in the presence of the ACTH analog compared to unmodified ACTH, (2) reduction of corticosteroid secretion by adrenal membrane in the presence of endogenous ACTH and (3) increased MC-2R binding affinity with reduced activation of the MC-2R receptor compared to unmodified ACTH binding to the MC-2R melanocortin. The ACTH analog compounds of the present invention are therefore useful for treatment or prevention of diseases and disorders related to ACTH, ACTH receptors or corticosteroid secretion, such as premature labor and Cushing's Disease.

Description

[0001] governmental support [0002] The subject of this application was supported by a research grant from the National Institutes of Health (Grant No. NIH: DK50870) and a grant from the National Science Foundation (Grant No. NSF IBN-0132210). Accordingly, the Government has certain rights in this invention. [0003] Cross References to Related Applications [0004] This application claims the benefit of U.S. Provisional Patent Application Serial No. 60 / 622,436, entitled "Compositions and Method Compositions for Treating Preterm Labor, Cushing's Syndrome, and Related Disorders," filed October 27, 2004, which provides The patent application is hereby incorporated by reference. technical field [0005] The present invention relates to ACTH analog compounds and related pharmaceutical compositions and methods of treatment. Background of the invention [0006] Corticotropin, also known as adrenocorticotropic hormone (ACTH), is the major hormone secreted by the pituitary gland...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K38/16A61K38/35
CPCA61K38/00C07K14/695A61K38/22A61P13/12A61P15/06A61P35/00A61P43/00A61P5/00A61P5/08A61P5/10A61P5/38A61P5/42A61P5/46A61K38/35A61K38/16
Inventor M·B·布伦南R·M·多里斯C·哈斯克尔-吕瓦诺U·H·霍切格施文德J·I·科斯塔
Owner UNIVERSITY OF DENVER
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