Glucocorticoids WONDRAK 2022.pdf

Medicinal Chemistry of Adrenocorticoids 1 Steroid Drugs Targeting the HPA-axis: Hypothalamic-pituitary-adrenal regulation HP: hypothalamus CRF: corticotropin releasing factor AP: anterior pituitary ACTH: adrenocorticotropic hormone AC: adrenal cortex HC: hydrocortisone 2 hydrocortisone = cortisol Gl...

Medicinal Chemistry of Adrenocorticoids 1 Steroid Drugs Targeting the HPA-axis: Hypothalamic-pituitary-adrenal regulation HP: hypothalamus CRF: corticotropin releasing factor AP: anterior pituitary ACTH: adrenocorticotropic hormone AC: adrenal cortex HC: hydrocortisone 2 hydrocortisone = cortisol Glucocorticoid Neuroendocrinology glucocorticoid effects: ‘pleiotropic’ anti-inflammatory immunosuppressive gluconeogenetic lipolytic catabolic [muscle/bone/skin] hypertensive euphoric N. Engl. J. Med. 2005, 353, 1711-1723 3 Adrenocorticoid signaling Glucocorticoid receptor DNA binding domain (DBD) [with Zinc fingers; Zinc atoms in yellow] CBG: corticosteroid binding globulin Hsp90: heat shock protein 90 GRE: glucocorticoid response element 4 Targeting Inflammatory Mediators: The Cortisol-Lipocortin-Phospholipase A2-Arachidonic Acid-Prostaglandin Chain - lipocortin glucocorticoids 5 Glucocorticoids: Important Immunosuppressive Drugs immunosuppressive drugs TCR cyclosporine mAB Glucocorticoids Calcineurin-inhibitors synthesis Glucocorticoids cyclophosphamide mycophenolate receptor azathioprine methotrexate cell proliferation site 6 mTOR-inhibitors cytostatic agents Therapeutic Indications for Glucocorticoids 7 Steroid Drugs: From Endogenous Ligand to Pharmaceutical Agent Optimization hydrocortisone [cortisol] through Medicinal Chemistry - potency - specificity 17b-estradiol - dissociated ligands - toxicity - duration of action - oral bioavailability - etc. 8 17a-ethinylestradiol Glucorticoid-GCR Interaction: Implications for SAR: Medicinal chemistry for optimization of potency, dissociation of glucoand mineralocorticoid activity, and metabolic stability etc. substituents involved in cortisol activity 9 Natural and Synthetic Corticosteroids 10 Adrenocorticoid Interconversion & Deactivation active inactive inactive inactive inactive inactive 11 Adrenocorticoid SAR 12 Natural and Synthetic Corticosteroids 13 1-Dehydroderivatives: Increased Anti-inflammatory Activity bioreductive activation 4x glucocorticoid acitivity, 0.5x mineralocorticoid activity [versus cortisol] prodrug Prednisone is a prodrug (11-keto group is converted into 11b-hydroxyl group; essential for hydrogen bond to Asn-564); prednisone should not be used in patients with hepatic insufficiency due (impaired bioconversion). 14 Exam question 1. cortisone 2. prednisolone 3. cortisol Three corticosteroid-type ligands are shown above. Indicate their relative glucocorticoid potency: A. 1 = 2 = 3. B. 1 > 2 > 3. C. 1 < 2 < 3. D. 2 > 3 > 1. E. 3 > 1 > 2. 15 Triamcinolone: Intermediate-acting halogen-substituted glucocorticoid Triamcinolone = 9a-fluoro-16ahydroxy-prednisolone Electronegative halogen, increases 11b-OH acidity >>> enhanced hydrogen bonding [GCR - Asn564] 16 in addition: D-ring substituents prolong duration of action