Craig D. Boyle

11β-hydroxysteroid dehydrogenase type 1 inhibitors: a review of recent patents

Background: The main components of metabolic syndrome (obesity, insulin resistance, hypertension and dyslipidemia) have become prevalent worldwide, and excess glucocorticoid levels have been implicated in patients with these symptoms. 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) is an enzyme involved in glucocorticoid regulation through catalysis of the conversion of inactive cortisone to its active form cortisol. Numerous rodent studies have demonstrated the potential use of 11β-HSD1 inhibitors as treatment for the components of metabolic syndrome and limited clinical data in humans have shown 11β-HSD1 inhibition to improve glucose levels, insulin sensitivity and lipid profiles. Many organizations have been active in the 11β-HSD1 academic and patent literature, and two previous articles from this journal have reviewed disclosures through August 2007. Objective: To summarize the recent patent literature and progress in defining the utility of small molecule 11β-HSD1 inhibitors. Methods: This review covers the recent 11β-HSD1 patent literature and clinical activity ranging from late 2007 through the end of 2008. Results/conclusion: The exploration of 11β-HSD1 inhibitors continues, as a number of structural classes have been reported by several pharmaceutical companies over the past 16 months. Current clinical trials will ultimately shed light on the feasibility of 11β-HSD1 inhibitors as pharmaceutical agents for the various components of metabolic syndrome.

Design and synthesis of xanthine analogues as potent and selective PDE5 inhibitors.

We have discovered potent and selective xanthine PDE5 inhibitors. Compound 25 (PDE5 IC(50)=0.6 nM, PDE6/PDE5=101) demonstrated similar functional efficacy and PK profile to Sildenafil (PDE5 IC(50)=3.5 nM, PDE6/PDE5=7).

Biaryl and heteroaryl derivatives of SCH 58261 as potent and selective adenosine A2A receptor antagonists.

SCH 58261 is a reported adenosine A(2A) receptor antagonist, which is active in rat in vivo models of Parkinsons Disease upon ip administration. However, it has poor selectivity versus the A(1) receptor and does not demonstrate oral activity. We report the design and synthesis of biaryl and heteroaryl analogs of SCH 58261 which improve the A(2A) receptor binding selectivity as well as the pharmacokinetic properties of SCH 58261. In particular, the quinoline 25 has excellent A(2A) receptor in vitro binding affinity and selectivity, sustained rat plasma levels upon oral dosing, and is active orally in a rat behavioral assay.

Design, synthesis, and evaluation of fused heterocyclic analogs of SCH 58261 as adenosine A2A receptor antagonists

SCH 58261 is a reported adenosine A(2A) receptor antagonist which is active in rat in vivo models of Parkinsons Disease upon ip administration. However, it has poor selectivity versus the A(1) receptor and does not demonstrate oral activity. Quinoline analogs have improved upon the selectivity and pharmacokinetics of SCH 58261, but were difficult to handle due to poor aqueous solubility. We report the design and synthesis of fused heterocyclic analogs of SCH 58261 with aqueous solubility as well as improved A(2A) receptor binding selectivity and pharmacokinetic properties. In particular, the tetrahydronaphthyridine 4s has excellent A(2A) receptor in vitro binding affinity and selectivity, is active orally in a rat in vivo model of Parkinsons Disease, and has aqueous solubility of 100 microM at physiological pH.

Benzylidene ketal derivatives as M2 muscarinic receptor antagonists

Benzylidene ketal derivatives were investigated as selective M2 receptor antagonists for the treatment of Alzheimers disease. Compound 10 was discovered to have subnanomolar M2 receptor affinity and 100-fold selectivity against other muscarinic receptors. Also, 10 demonstrated in vivo efficacy in rodent models of muscarinic activity and cognition.

Metabolic stabilization of benzylidene ketal M2 muscarinic receptor antagonists via halonaphthoic acid substitution

The potential toxicological liabilities of the M(2) muscarinic antagonist 1 were addressed by replacing the methylenedioxyphenyl moiety with a p-methoxyphenyl group, resulting in M(2) selective compounds such as 3. Several halogenated naphthamide derivatives of 3 were studied in order to improve the pharmacokinetic profile via blockage of oxidative metabolism. Compound 4 demonstrated excellent M(2) affinity and selectivity, human microsomal stability, and oral bioavailability in rodents and primates.

The discovery of azepane sulfonamides as potent 11β-HSD1 inhibitors

Discovery of a series of azepine sulfonamides as potent inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) is described. SAR studies at the 4-position of the azepane ring have resulted in the discovery of a very potent compound 30 which has an 11beta-HSD1 IC(50) of 3.0nM.

Enhancement of pharmacokinetic properties and in vivo efficacy of benzylidene ketal M2 muscarinic receptor antagonists via benzamide modification

We previously reported the initial discovery of a novel class of stabilized benzylidene ketal M(2) receptor antagonists. This paper discusses new analogues consisting of benzamide modifications which not only improved M(2) receptor affinity and selectivity, but also enhanced the pharmacokinetic properties of the series. These changes led to the discovery of a highly potent and selective M(2) antagonist, which demonstrated in vivo efficacy and had good bioavailability in multiple species.

11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitors

Publisher Summary Human 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is a 292-amino-acid glycosylated protein with a single N-terminal transmembrane segment that anchors the catalytic domain in the lumen of the endoplasmic reticulum (ER). It is widely distributed with high expression in active glucocorticoid receptor (GR) tissues such as liver, adipose, and brain. In intact cells, 11β-HSD1 acts largely as a glucocorticoid reductase driven by the redox potential maintained by the reduced nicotinamide adenine dinucleotide phosphate (NADPH) generating enzyme hexose-6-phosphate dehydrogenase (H6PDH) in the ER compartment. Thiazoles, triazoles, amides, and some miscellaneous derivatives have demonstrated 11β-HSD1. One of the first classes of 11β-HSD1 inhibitors to demonstrate selectivity over 11β-HSD2 consisted of thiazole analogs. The general structure of active thiazoles incorporates a sulfonamide moiety at the 2-position of the thiazole ring. Triazoles are another highly studied class of 11β-HSD1 inhibitors—for example, adamantyl triazoles have been recently reported as potent and selective 11β-HSD1 inhibitors. In addition, different amide-based structures have also been explored as 11β-HSD1 inhibitors.