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Nephrology Lab · DeCure for X

DeCure for Chronic primary adrenal insufficiency

DeCure's autonomous Nephrology AI scientist is researching a drug-repurposing hypothesis for chronic primary adrenal insufficiency — screening already-approved drugs against its 21-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.

Disease module21 genesLead labNephrology
All cures
NephrologyDOID:13774$DeCureNephro

The disease map

Disease moduleChronic primary adrenal insufficiency maps to a 21-gene Open Targets module — the target space DeCure's AI scientist screens approved drugs against.
DeCure.ai methodSignature reversal (LINCS) plus network proximity (STRING) rank already-approved drugs likely to perturb this module — the same engine that produces DeCure.ai's repurposing hypotheses.
Repurposing thesisScreening approved medicines against this disease module, then publishing the evidence for the strongest candidate. Known pharmacology and human exposure data make the first question sharper — they do not establish safety or efficacy in a new indication.

Research record

01
ResearchComing soon
Candidate research + dossier — target rationale, drug-repurposing thesis and evidence pack.proof: Published dossier + on-chain hash
02
ValidationComing soon
In-vitro biological validation at a contract research org (CRO).proof: CRO contract + in-vitro report
03
Peer review & paperComing soon
Peer-reviewed paper published open-access (preprint + journal).proof: DOI + open-access link + on-chain hash

Current lead

No approved-drug candidate for chronic primary adrenal insufficiency is corroborated in the literature DeepSearch retrieved. Some conditions are managed with non-pharmacological care — a device, surgery or physical therapy — rather than a medicine; that may be the case here, or the literature we found may simply be too sparse yet to support a drug-repurposing angle.

Molecular view

nuclear receptor subfamily 3 group C member 2 (NR3C2) — NR3C2 is one of the genes genetically linked to this disease in Open Targets — shown as context, not as a drug target we're pursuing: no approved-drug candidate for this disease is yet corroborated in the literature we found.

Loading structure…
helix sheet 2,2-difluoro-3-hydroxypropyldrag to rotate · scroll to zoom

RCSB Protein Data Bank · entry 4PF3 · 1.1 Å · ligand 6-[1-(2,2-difluoro-3-hydroxypropyl)-5-(4-fluorophenyl)-3-methyl-1H-pyrazol-4-yl]-2H-1,4-benzoxazin-3(4H)-one (HFN). Experimental structure, not a prediction.

What the evidence adds up to

In chronic primary adrenal insufficiency, the core treatment remains replacement of adrenocortical steroids. A 1953 review states that these hormones "are capable of restoring severely ill patients to a state of health that is remarkably near normal," but it also notes that "the indications for their use and their ultimate place in the therapeutic armamentarium are not yet clearly defined" and that "unusual care" is needed when starting or stopping such therapy. No survival or response rates are given in that abstract.

By 1997, the clinical spectrum of primary adrenal insufficiency had changed. The editorial describes that more than 50% of patients with AIDS have pathological evidence of necrotizing adrenalitis, though the degree of adrenal destruction is usually less than 50%. It also lists emerging challenges including adrenal insufficiency in the antiphospholipid antibody syndrome, autoimmune polyendocrine syndromes, X-linked adrenoleukodystrophy, and mutations of the ACTH receptor gene. No new treatments are proposed; the editorial focuses on recognition of these new causes.

A 2024 review defines adrenal insufficiency as a defect along the hypothalamic-pituitary-adrenal axis causing deficiency in one or more adrenal hormones, primarily cortisol. It divides the condition into primary, secondary, and tertiary forms. Autoimmune primary adrenal insufficiency is noted as the common form, but no new therapeutic data are presented.

A 2025 metabolomics study in asthma patients on inhaled corticosteroids identified 12 metabolites significantly associated with adrenal suppression after correction for multiple comparisons. In a validation cohort of 575 patients, only 3 replicated: tetrahydrocortisol glucuronide, tetrahydrocortisol glucuronide (5), and homocitrulline. Pathway analysis pointed to alterations in steroid, bile acid, urea cycle, and long-chain polyunsaturated fatty acid metabolism. This study does not address primary adrenal insufficiency directly, and no intervention is tested.

Evidence

Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.

New England Journal of Medicine · 1953 · 157 citations

Pharmacologic Aspects of Adrenocortical Steroids and ACTH in Man

AbstractTHE importance of the adrenocortical steroids as essential mediators of metabolic processes is well established. In the treatment of adrenocortical insufficiency these hormones are capable of restoring severely ill patients to a state of health that is remarkably near normal. In the wider field of inflammatory diseases their action is no less dramatic, although the indications for their use and their ultimate place in the therapeutic armamentarium are not yet clearly defined. Experience has emphasized the necessity for exercising unusual care in initiating or terminating a therapeutic trial with these agents. Regardless of the extent to which they may eventually . . .

https://doi.org/10.1056/nejm195302052480604
Annals of Internal Medicine · 1997 · 34 citations

The Changing Clinical Spectrum of Adrenal Insufficiency

AbstractEditorials15 December 1997The Changing Clinical Spectrum of Adrenal InsufficiencyRobert M. Carey, MDRobert M. Carey, MDUniversity of Virginia School of Medicine; Charlottesville, VA 22908.Author, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-127-12-199712150-00009 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail The clinical spectrum of primary adrenal insufficiency has changed substantially over the past decade as a result of the emergence of new disease patterns, improved understanding of clinical presentations, and the impact of molecular genetics. I comment here on five clinical entities that have emerged as new diagnostic or therapeutic challenges in the 1990s.Adrenal insufficiency is increasingly recognized in patients with AIDS [1-3], and it correlates with stage of progression of HIV infection. More than 50% of patients with AIDS have pathologic evidence of necrotizing adrenalitis, but the degree of adrenal destruction is usually less than 50%. Clinical adrenal ...References1. Piedrola G, Casado JL, Lopez E, Moreno A, Perez-Elias MJ, Garcia-Robles R. Clinical features of adrenal insufficiency in patients with acquired immunodeficiency syndrome. Clin Endocrinol (Oxf). 1996; 45:97-101. Google Scholar2. Freda PU, Wardlaw SL, Brudney K, Goland RS. Primary adrenal insufficiency in patients with the acquired immunodeficiency syndrome: a report of five cases. J Clin Endocrinol Metab. 1994; 79:1540-5. Google Scholar3. Amason JA, Graziano FM. Adrenal insufficiency in the antiphospholipid antibody syndrome. Semin Arthritis Rheum. 1995; 25:109-16. Google Scholar4. Bevilacqua M. Hyponatremia in AIDS. Baillieres Clin Endocrinol Metab. 1994; 8:837-48. Google Scholar5. May ME, Vaughan ED Jr, Carey RM. Adrenocortical insufficiency-clinical aspects. In: Vaughan ED Jr, Carey RM, eds. Adrenal Disorders. New York: Thieme Medical; 1989:171-89. Google Scholar6. Burke CW. Adrenocortical insufficiency. Clin Endocrinol Metab. 1985; 14:947-76. Google Scholar7. Chin R. Adrenal crisis. Crit Care Clin. 1991; 7:23-42. Google Scholar8. Siu SC, Kitzman DW, Sheedy PF 2d, Northcutt RC. Adrenal insufficiency from bilateral adrenal hemorrhage. Mayo Clin Proc. 1990; 65:664-70. Google Scholar9. Winqvist O, Gustafsson J, Rorsman F, Karlsson FA, Kampe O. Two different cytochrome P450 enzymes are the adrenal antigens in autoimmune polyendocrine syndrome type I and Addison's disease. J Clin Invest. 1993; 92:2377-85. Google Scholar10. Uibo R, Aavik E, Peterson P, Perheentupa J, Aranko S, Pelkonen R, et al. Autoantibodies to cytochrome P450 enzymes P450scc, P450c17, and P450c21 in autoimmune polyglandular disease types I and II and in isolated Addison's disease. J Clin Endocrinol Metab. 1994; 78:323-8. Google Scholar11. Winqvist O, Gebre-Medhin G, Gustafsson J, Ritzen EM, Lundkvist O, Karlsson FA, et al. Identification of the main gonadal autoantigens in patients with adrenal insufficiency and associated ovarian failure. J Clin Endocrinol Metab. 1995; 80:1717-23. Google Scholar12. Chen S, Sawicka J, Betterle C, Powell M, Prentice L, Volpato M, et al. Autoantibodies to steroidogenic enzymes in autoimmune polyglandular syndrome, Addison's disease, and premature ovarian failure. J Clin Endocrinol Metab. 1996; 8:1871-6. Google Scholar13. Furmaniak J, Kominami S, Asawa T, Wedlock N, Colls J, Smith BR. Autoimmune Addison's disease-evidence for a role of steroid 21-hydroxylase autoantibodies in adrenal insufficiency. J Clin Endocrinol Metab. 1994; 79:1517-21. Google Scholar14. Boscaro M, Betterle C, Sonino N, Volpato M, Paoletta A, Fallo F. Early adrenal hypofunction in patients with organ-specific autoantibodies and no clinical adrenal insufficiency. J Clin Endocrinol Metab. 1994; 79:452-5. Google Scholar15. De Bellis A, Bizzarro A, Rossi R, Paglionico VA, Criscuolo T, Lombardi G, et al. Remission of subclinical adrenocortical failure in subjects with adrenal autoantibodies. J Clin Endocrinol Metab. 1993; 76:1002-7. Google Scholar16. Moser HW. Adrenoleukodystrophy. Curr Opin Neurol. 1995; 8:221-6. Google Scholar17. Aubourg P. Adrenoleukodystrophy and other peroxisomal diseases. Curr Opin Genet Dev. 1994; 4:407-11. Google Scholar18. Wanders RJ, Schutgens RB, Barth PG. Peroxisomal disorders: a review. J Neuropathol Exp Neurol. 1995; 54:726-39. Google Scholar19. Blevins LS Jr, Shankroff J, Moser HW, Ladenson PW. Elevated plasma adrenocorticotropin concentration as evidence of limited adrenocortical reserve in patients with adrenomyeloneuropathy. J Clin Endocrinol Metab. 1994; 78:261-5. Google Scholar20. Laureti S, Casucci G, Santeusanio F, Angeletti G, Aubourg P, Brunetti P. X-linked adrenoleukodystrophy is a frequent cause of idiopathic Addison's disease in young adult male patients. J Clin Endocrinol Metab. 1996; 81:470-4. Google Scholar21. Tsigos C, Arai K, Latronico AC, DiGeorge AM, Rapaport R, Chrousos GP. A novel mutation of the adrenocorticotropin receptor (ACTH-R) gene in a family with the syndrome of isolated glucocorticoid deficiency, but no ACTH-R abnormalities in two families with the triple A syndrome. J Clin Endocrinol Metab. 1995; 80:2186-9. Google Scholar22. Weber A, Clark AJ. Mutations of the ACTH receptor gene are only one cause of familial glucocorticoid deficiency. Hum Mol Genet. 1994; 3:585-8. Google Scholar Author, Article, and Disclosure InformationAffiliations: University of Virginia School of Medicine; Charlottesville, VA 22908.Corresponding Author: Robert M. Carey, MD, Box 395, University of Virginia Health Sciences Center, Charlottesville, VA 22908. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited byNeuromuscular Manifestations of Acquired Metabolic, Endocrine, and Nutritional DisordersSteroid Therapy in Adrenal InsufficiencyClinical implications for biochemical diagnostic thresholds of adrenal sufficiency using a highly specific cortisol immunoassayThe Adrenal CortexNeurologic complications of disorders of the adrenal glandsNeurologic complications of multiple endocrine syndromesCardiovascular Manifestations of Endocrine DysfunctionThe Adrenal CortexNeuromuscular Manifestations of Acquired Metabolic, Endocrine, and Nutritional DisordersAddison's Disease From Non-Hodgkin's Lymphoma With Normal-Size Adrenal GlandsCT diagnosis of acute adrenal insufficiency due to bilateral adrenal haemorrhageNeurohormonal FactorsRecognition and Management of Adrenal EmergenciesAdrenal hemorrhage mimicking an acute abdomenAntiphospholipid syndrome and endocrine damage: why bilateral adrenal thrombosis?Autoantibodies in autoimmune polyendocrine syndrome type IIAdrenal Insufficiency in Critically Ill PatientsPrimary hypoadrenalism assessed by the 1 μg ACTH test in hospitalized patients with active pulmonary tuberculosis 15 December 1997Volume 127, Issue 12Page: 1103-1105KeywordsAIDSAdrenocorticotropic hormoneAutoantibodiesCholesterolEnzymesFatty acidsHemorrhageSteroidogenesisThrombosisType 1 diabetes Issue Published: 15 December 1997 Copyright & PermissionsCopyright © 1997 by American College of Physicians. 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https://doi.org/10.7326/0003-4819-127-12-199712150-00009
PEDIATRICS · 1981 · 27 citations

Management of Pituitary-Adrenal Suppression Secondary to Corticosteroid Therapy

AbstractWithdrawal of steroid medications from patients who have been receiving them for management of chronic disease carries the risk of certain serious complications. An understanding of adrenal physiology, coupled with a rational plan for evaluating the individual patient, when necessary, and for protecting against certain stressful situations, should obviate the occurrence of acute adrenal insufficiency.

https://doi.org/10.1542/peds.67.2.245
Journal of Allergy and Clinical Immunology · 2025 · 2 citations · open access

Plasma pharmacometabolomics of inhaled corticosteroid–related adrenal suppression in asthma

AbstractBACKGROUND: Inhaled corticosteroids (ICSs) are frequently prescribed medications for asthma symptoms, but higher doses can increase risks of adrenal insufficiency through suppression of endogenous cortisol production. Understanding which patients may be at increased risk for developing adrenal suppression related to ICS use may help providers improve treatment regimens for asthmatic patients; however, the mechanisms underlying ICS-related adrenal insufficiency have not been clarified. OBJECTIVE: We sought to identify metabolite signatures and biochemical pathways associated with ICS-related adrenal insufficiency in asthmatic patients. METHODS: Global metabolite profiling (metabolomics) was integrated with electronic medical records data including the development of adrenal suppression in 2 independent asthma cohorts. The discovery cohort (Pharmacogenomics of Adrenal Suppression with Inhaled Corticosteroids) included 711 adult asthmatic patients on ICSs. Untargeted metabolomic profiling identified 1397 metabolites, of which 810 were selected for further analysis. Using plasma cortisol as a biomarker for adrenal status (outcome), linear regression models were used to identify associations between metabolites and plasma cortisol, adjusted for potential confounders. In the validation cohort (Omics Determinant of Longitudinal Lung Function in Asthma Study), metabolite associations were validated in 575 patients on ICSs. Pathway and network analyses were performed using bioinformatic approaches to identify altered metabolic pathways related to the outcome. RESULTS: Of 810 endogenous metabolites, 12 demonstrated significant associations with adrenal insufficiency after correction for multiple comparisons. In the validation cohort, 3 of these 12 replicated, including 2 steroid metabolites (tetrahydrocortisol glucuronide and tetrahydrocortisol glucuronide (5)) and homocitrulline. Pathway and network analyses revealed alterations in biochemical pathways related to the metabolism of steroids, bile acids, urea cycle, and long-chain polyunsaturated fatty acids. CONCLUSIONS: We have identified specific metabolites within steroid and nonsteroid metabolic pathways that are associated with adrenal insufficiency with ICS use.

https://doi.org/10.1016/j.jaci.2025.02.037
Pharmaceutical journal/˜The œpharmaceutical journal · 2024 · 0 citations · open access

Adrenal insufficiency: pathophysiology, diagnosis and management

AbstractThe term ‘adrenal insufficiency’ refers to a group of conditions that all result from a defect along the hypothalamic-pituitary-adrenal (HPA) axis and subsequent deficiency in one or more of the adrenal hormones, primarily cortisol. It can be divided into primary, secondary and tertiary forms, depending on the underlying cause​1​. Autoimmune primary adrenal insufficiency, commonly known […]

https://doi.org/10.1211/pj.2024.1.338894

Disease module: DeepOracle (Open Targets). Structures: RDKit from PubChem SMILES. Literature: retrieved by DeepSearch across 234,678,978 indexed works (targeted per-candidate search), resolved on OpenAlex.

DeCure is a research and publication project, not medical advice and not a treatment. "DeCure for X" describes a research goal, not a claim that a cure exists. Backing a cure is a contribution to fund the research — it is not an investment, and confers no yield, royalty, equity or IP ownership. Papers are published open-access by the DeCure.ai DAO.