title: Design, synthesis, and evaluation of (2S,4R)-Ketoconazole sulfonamide analogs as potential treatments for Metabolic Syndrome.
abstract: Metabolic Syndrome, also referred to as 'Syndrome X' or 'Insulin Resistance Syndrome,' remains a major, unmet medical need despite over 30years of intense effort. Recent research suggests that there may be a causal link between this condition and abnormal glucocorticoid processing. Specifically, dysregulation of the hypothalamic-pituitary-adrenocortical (HPA) axis leads to increased systemic cortisol concentrations. Cushing' syndrome, a disorder that is also typified by a marked elevation in levels of cortisol, produces clinical symptomology that is similar to those observed in MetS, and they can be alleviated by decreasing circulating cortisol concentrations. As a result, it has been suggested that decreasing systemic cortisol concentration might have a positive impact on the progression of MetS. This could be accomplished through inhibition of enzymes in the cortisol synthetic pathway, 11β-hydroxylase (Cyp11B1), 17α-hydroxylase-C17,20-lyase (Cyp17), and 21-hydroxylase (Cyp21). We have identified a series of novel sulfonamide analogs of (2S,4R)-Ketoconazole that are potent inhibitors of these enzymes. In addition, selected members of this class of compounds have pharmacokinetic properties consistent with orally delivered drugs, making them well suited to further investigation as potential therapies for MetS.
authors: Moulder Center for Drug Discovery Research, Temple University School of Pharmacy, 3307 N Broad Street, Philadelphia, PA 19140, USA. Electronic address: Benjamin.Blass@Temple.edu.
authors: Benjamin E
authors: BE
authors: Blass
authors: GVK Biosciences Private Limited, Plot 28A, IDA Nacharam, Hyderabad 500076, India.
authors: Pravin
authors: P
authors: Iyer
authors: Moulder Center for Drug Discovery Research, Temple University School of Pharmacy, 3307 N Broad Street, Philadelphia, PA 19140, USA.
authors: Magid
authors: M
authors: Abou-Gharbia
authors: Moulder Center for Drug Discovery Research, Temple University School of Pharmacy, 3307 N Broad Street, Philadelphia, PA 19140, USA.
authors: Wayne E
authors: WE
authors: Childers
authors: Moulder Center for Drug Discovery Research, Temple University School of Pharmacy, 3307 N Broad Street, Philadelphia, PA 19140, USA.
authors: John C
authors: JC
authors: Gordon
authors: Moulder Center for Drug Discovery Research, Temple University School of Pharmacy, 3307 N Broad Street, Philadelphia, PA 19140, USA.
authors: Mercy
authors: M
authors: Ramanjulu
authors: Moulder Center for Drug Discovery Research, Temple University School of Pharmacy, 3307 N Broad Street, Philadelphia, PA 19140, USA.
authors: George
authors: G
authors: Morton
authors: GVK Biosciences Private Limited, Plot 28A, IDA Nacharam, Hyderabad 500076, India.
authors: Premkumar
authors: P
authors: Arumugam
authors: GVK Biosciences Private Limited, Plot 28A, IDA Nacharam, Hyderabad 500076, India.
authors: Joshodeep
authors: J
authors: Boruwa
authors: GVK Biosciences Private Limited, Plot 28A, IDA Nacharam, Hyderabad 500076, India.
authors: John
authors: J
authors: Ellingboe
authors: GVK Biosciences Private Limited, Plot 28A, IDA Nacharam, Hyderabad 500076, India.
authors: Sayan
authors: S
authors: Mitra
authors: GVK Biosciences Private Limited, Plot 28A, IDA Nacharam, Hyderabad 500076, India.
authors: Rajashekar Reddy
authors: RR
authors: Nimmareddy
authors: GVK Biosciences Private Limited, Plot 28A, IDA Nacharam, Hyderabad 500076, India.
authors: Shalini
authors: S
authors: Paliwal
authors: GVK Biosciences Private Limited, Plot 28A, IDA Nacharam, Hyderabad 500076, India.
authors: Jamallamudi
authors: J
authors: Rajasekhar
authors: GVK Biosciences Private Limited, Plot 28A, IDA Nacharam, Hyderabad 500076, India.
authors: Savithiri
authors: S
authors: Shivakumar
authors: GVK Biosciences Private Limited, Plot 28A, IDA Nacharam, Hyderabad 500076, India.
authors: Pratima
authors: P
authors: Srivastava
authors: GVK Biosciences Private Limited, Plot 28A, IDA Nacharam, Hyderabad 500076, India.
authors: Raghuram S
authors: RS
authors: Tangirala
authors: GVK Biosciences Private Limited, Plot 28A, IDA Nacharam, Hyderabad 500076, India.
authors: Konda
authors: K
authors: Venkataramanaiah
authors: GVK Biosciences Private Limited, Plot 28A, IDA Nacharam, Hyderabad 500076, India.
authors: Mahesh
authors: M
authors: Yanamandra
mesh_terms: D000818:Animals; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D015195:Drug Design; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D007654:Ketoconazole / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D024821:Metabolic Syndrome / Q000188:drug therapy* / Q000201:enzymology; D013449:Sulfonamides / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D013449:Sulfonamides; D007654:Ketoconazole
keywords: 17α‐Hydroxylase‐C17,20‐lyase (Cyp17); Cortisol; Ketoconazole; Metabolic Syndrome