title: Novel functionalized 5-(phenoxymethyl)-1,3-dioxane analogs exhibiting cytochrome P450 inhibition: a patent evaluation WO2015048311 (A1).
abstract: Cytochrome P450's (CYP's) constitute a diverse group of over 500 monooxygenase hemoproteins, catalyzing transformations that involve xenobiotic metabolism, steroidogenesis and other metabolic processes. Over-production of the steroid hormone cortisol is implicated in the progression of diseases such as diabetes, heart failure and hypertension, stroke, Cushing's syndrome, obesity and renal failure, among others. The biosynthesis of cortisol involves a cascade of cholesterol metabolizing reactions regulated through three major CYP proteins: 17α-hydroxylase-C17/20-lyase (CYP17), 21-hydroxylase (CYP21), and 11β-hydroxylase (CYP11B1). Excess activities of these enzymes are linked to the progression of malignancies including prostate, breast, ovarian, and uterine cancers. A series of novel functionalized dioxane analogs have been developed and recently patented as CYP17, CYP21, and CYP11B1 inhibitors, which lead to the modulation of cortisol production as a method for treating, delaying, slowing, and inhibiting the implicated diseases. The findings disclosed in this patent have been analyzed and compared with the literature data on inhibitors of CYP17, CYP21, and CYP11B1. The compiled data provide insight into the novel functionality of the compounds described in the patent. In this regard, an objective opinion on the effectiveness and novel biochemistry of these compounds in comparison to current CYP inhibitors used in the treatment of cortisol-related diseases is presented in this paper.
authors.affiliation: a Department of Chemistry , Xavier University of Louisiana , New Orleans , LA , USA.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Schroeder
authors.affiliation: a Department of Chemistry , Xavier University of Louisiana , New Orleans , LA , USA.
authors.forename: Phan
authors.initials: P
authors.lastname: Tram
authors.affiliation: a Department of Chemistry , Xavier University of Louisiana , New Orleans , LA , USA.
authors.forename: Jiawang
authors.initials: J
authors.lastname: Liu
authors.affiliation: a Department of Chemistry , Xavier University of Louisiana , New Orleans , LA , USA.
authors.forename: Maryam
authors.initials: M
authors.lastname: Foroozesh
authors.affiliation: a Department of Chemistry , Xavier University of Louisiana , New Orleans , LA , USA.
authors.forename: Jayalakshmi
authors.initials: J
authors.lastname: Sridhar
mesh_terms: D065607:Cytochrome P-450 Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D004146:Dioxanes / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism*; D010330:Patents as Topic; D013252:Steroid 11-beta-Hydroxylase / Q000037:antagonists & inhibitors / Q000378:metabolism; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors / Q000378:metabolism; D013255:Steroid 21-Hydroxylase / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D004146:Dioxanes; D013255:Steroid 21-Hydroxylase; D013254:Steroid 17-alpha-Hydroxylase; D013252:Steroid 11-beta-Hydroxylase; C025223:1,4-dioxane; D006854:Hydrocortisone
keywords: CYP11; CYP17; CYP21; P450 inhibition; cortisol; cytochrome P450