Discovery of a potent, selective, and orally bioavailable acidic 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitor: discovery of 2-[(3S)-1-[5-(cyclohexylcarbamoyl)-6-propylsulfanylpyridin-2-yl]-3-piperidyl]acetic acid (AZD4017).

Inhibition of 11β-HSD1 is an attractive mechanism for the treatment of obesity and other elements of the metabolic syndrome. We report here the discovery of a nicotinic amide derived carboxylic acid class of inhibitors that has good potency, selectivity, and pharmacokinetic characteristics. Compound 11i (AZD4017) is an effective inhibitor of 11β-HSD1 in human adipocytes and exhibits good druglike properties and as a consequence was selected for clinical development.

[1]  E. Walker,et al.  11β-Hydroxysteroid dehydrogenase: unexpected connections , 2003, Trends in Endocrinology & Metabolism.

[2]  Claude Lenfant,et al.  Definition of Metabolic Syndrome: Report of the National Heart, Lung, and Blood Institute/American Heart Association Conference on Scientific Issues Related to Definition , 2004, Arteriosclerosis, thrombosis, and vascular biology.

[3]  P. Leeson,et al.  The influence of drug-like concepts on decision-making in medicinal chemistry , 2007, Nature Reviews Drug Discovery.

[4]  E. Lai,et al.  Effects of an 11β‐hydroxysteroid dehydrogenase type 1 inhibitor, MK‐0916, in patients with type 2 diabetes mellitus and metabolic syndrome , 2011, Diabetes, obesity & metabolism.

[5]  R. Benediktsson,et al.  11β-Hydroxysteroid dehydrogenases: Key enzymes in determining tissue-specific glucocorticoid effects , 1996, Steroids.

[6]  J. Tomlinson,et al.  11β-Hydroxysteroid dehydrogenase type 1 inhibitors for the treatment of type 2 diabetes , 2010, Expert opinion on investigational drugs.

[7]  G. Hollis,et al.  11β‐Hydroxysteroid dehydrogenase type 1 inhibition in type 2 diabetes mellitus , 2011, Diabetes, obesity & metabolism.

[8]  R. Thieringer,et al.  Inhibition of 11β-HSD1 as a novel treatment for the metabolic syndrome: do glucocorticoids play a role? , 2005, Expert review of cardiovascular therapy.

[9]  B. Walker,et al.  Effects of the 11β-Hydroxysteroid Dehydrogenase Inhibitor Carbenoxolone on Insulin Sensitivity in Men with Type 2 Diabetes , 2003 .

[10]  John C Lindon,et al.  Acyl glucuronides: biological activity, chemical reactivity, and chemical synthesis. , 2006, Journal of medicinal chemistry.

[11]  A. Fanjul,et al.  N-(Pyridin-2-yl) arylsulfonamide inhibitors of 11beta-hydroxysteroid dehydrogenase type 1: Discovery of PF-915275. , 2009, Bioorganic & medicinal chemistry letters.

[12]  L. Abrahmsén,et al.  Arylsulfonamidothiazoles as a new class of potential antidiabetic drugs. Discovery of potent and selective inhibitors of the 11beta-hydroxysteroid dehydrogenase type 1. , 2002, Journal of medicinal chemistry.

[13]  B. Walker.  Glucocorticoids and cardiovascular disease. , 2007, European journal of endocrinology.

[14]  Jeremy W Tomlinson,et al.  11 (cid:1) -Hydroxysteroid Dehydrogenase Type 1: A Tissue-Specific Regulator of Glucocorticoid Response , 2004 .

[15]  Philip D. McMaster,et al.  DO SPECIES LACKING A GALL BLADDER POSSESS ITS FUNCTIONAL EQUIVALENT? , 1922, The Journal of experimental medicine.

[16]  B. He,et al.  Effective dosing regimen of 1-aminobenzotriazole for inhibition of antipyrine clearance in rats, dogs, and monkeys. , 2002, Drug metabolism and disposition: the biological fate of chemicals.

[17]  M. New,et al.  A genetic defect resulting in mild low-renin hypertension. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[18]  Suresh B. Singh,et al.  Structure-based design and synthesis of 1,3-oxazinan-2-one inhibitors of 11β-hydroxysteroid dehydrogenase type 1. , 2011, Journal of medicinal chemistry.

[19]  J. Seckl,et al.  Inhibition of 11beta-hydroxysteroid dehydrogenase type 1 as a promising therapeutic target. , 2007, Drug discovery today.

[20]  Jiandong Zhang,et al.  Discovery of a potent, orally active 11beta-hydroxysteroid dehydrogenase type 1 inhibitor for clinical study: identification of (S)-2-((1S,2S,4R)-bicyclo[2.2.1]heptan-2-ylamino)-5-isopropyl-5-methylthiazol-4(5H)-one (AMG 221). , 2010, Journal of medicinal chemistry.

[21]  P. Björntorp,et al.  Hypothalamic arousal, insulin resistance and Type 2 diabetes mellitus , 1999, Diabetic medicine : a journal of the British Diabetic Association.

[22]  C. Edwards,et al.  Hypertension in mice lacking 11beta-hydroxysteroid dehydrogenase type 2. , 1999, The Journal of clinical investigation.

[23]  A B Atkinson,et al.  Diagnosis and complications of Cushing's syndrome: a consensus statement. , 2003, The Journal of clinical endocrinology and metabolism.

[24]  P. Björntorp,et al.  Obesity and cortisol. , 2000, Nutrition.

[25]  T. Kowalski,et al.  11β-hydroxysteroid dehydrogenase type 1 inhibitors: a review of recent patents , 2009, Expert opinion on therapeutic patents.

[26]  Y. Hirokawa,et al.  An efficient synthesis of 5-bromo-2-methoxy-6-methylaminopyridine-3carboxylic acid. , 2000, Chemical & pharmaceutical bulletin.

[27]  J. Strain,et al.  Cortisol production in obesity. , 1980, Metabolism: clinical and experimental.

[28]  P. Feig,et al.  Efficacy and safety of the selective 11β-HSD-1 inhibitors MK-0736 and MK-0916 in overweight and obese patients with hypertension. , 2011, Journal of the American Society of Hypertension : JASH.

[29]  J. Rosenstock,et al.  The 11-β-Hydroxysteroid Dehydrogenase Type 1 Inhibitor INCB13739 Improves Hyperglycemia in Patients With Type 2 Diabetes Inadequately Controlled by Metformin Monotherapy , 2010, Diabetes Care.

[30]  C. Edwards,et al.  11β-hydroxysteroid dehydrogenase 1 in adipocytes: Expression is differentiation-dependent and hormonally regulated , 1998, The Journal of Steroid Biochemistry and Molecular Biology.

[31]  T. Ebner,et al.  Disposition and chemical stability of telmisartan 1-O-acylglucuronide. , 1999, Drug metabolism and disposition: the biological fate of chemicals.

[32]  Scott P. Webster,et al.  11β-Hydroxysteroid dehydrogenase type 1 inhibitors as therapeutic agents , 2007 .

[33]  R. Foti,et al.  In vivo use of the P450 inactivator 1-aminobenzotriazole in the rat: varied dosing route to elucidate gut and liver contributions to first-pass and systemic clearance. , 2006, Journal of pharmaceutical sciences.