ABSTRACT
Inhibition of 11beta-HSD1 has demonstrated potential in the treatment of various components of metabolic syndrome. We wish to report herein the discovery of novel azabicyclic sulfonamide based 11beta-HSD1 inhibitors. Highly potent compounds exhibiting inhibitory activities at both human and mouse 11beta-HSD1 were identified. Several compounds demonstrated significant in vivo activity in the mouse cortisone challenge assay.
Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1/antagonists & inhibitors , Azabicyclo Compounds/chemistry , Enzyme Inhibitors/chemistry , Hypoglycemic Agents/chemistry , Sulfonamides/chemistry , 11-beta-Hydroxysteroid Dehydrogenase Type 1/metabolism , Animals , Cortisone/chemistry , Cortisone/metabolism , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Humans , Hypoglycemic Agents/chemical synthesis , Hypoglycemic Agents/pharmacology , Mice , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/pharmacologyABSTRACT
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.
Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1/antagonists & inhibitors , Anti-Inflammatory Agents/chemistry , Azepines/chemistry , Azepines/chemical synthesis , Enzyme Inhibitors/chemistry , Sulfonamides/chemistry , 11-beta-Hydroxysteroid Dehydrogenase Type 1/metabolism , Animals , Anti-Inflammatory Agents/chemical synthesis , Anti-Inflammatory Agents/pharmacology , Azepines/pharmacology , Drug Discovery , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Humans , Mice , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/pharmacologyABSTRACT
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. 11beta-Hydroxysteroid dehydrogenase type 1 (11beta-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 11beta-HSD1 inhibitors as treatment for the components of metabolic syndrome and limited clinical data in humans have shown 11beta-HSD1 inhibition to improve glucose levels, insulin sensitivity and lipid profiles. Many organizations have been active in the 11beta-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 11beta-HSD1 inhibitors. METHODS: This review covers the recent 11beta-HSD1 patent literature and clinical activity ranging from late 2007 through the end of 2008. RESULTS/CONCLUSION: The exploration of 11beta-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 11beta-HSD1 inhibitors as pharmaceutical agents for the various components of metabolic syndrome.
Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Metabolic Syndrome/drug therapy , Animals , Blood Glucose/drug effects , Clinical Trials as Topic , Humans , Insulin Resistance , Lipids/blood , Metabolic Syndrome/physiopathology , Patents as TopicABSTRACT
Glucocorticoids are steroid hormones that regulate several physiological processes, and modulation of glucocorticoid action has been implicated as a potential treatment for a variety of diseases, including metabolic syndrome, inflammation and age-related cognitive decline. 11b-Hydroxysteroid dehydrogenase type 1 (11b-HSD1) is an enzyme that is involved in glucocorticoid regulation by catalyzing the conversion of inactive cortisone to its active form cortisol. Rodent models have demonstrated that the inhibition of 11b-HSD1 can improve components of metabolic syndrome, such as insulin resistance and dyslipidemia, and several laboratories are exploring small-molecule 11b-HSD1 inhibitors as a treatment for metabolic syndrome, as well as for type 2 diabetes. This review discusses progress in the development of key chemical classes of 11b-HSD1 inhibitors, with a focus on advanced compounds and recently disclosed structures.
Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1/antagonists & inhibitors , Drug Design , Enzyme Inhibitors/pharmacology , Hypoglycemic Agents/pharmacology , 11-beta-Hydroxysteroid Dehydrogenase Type 1/metabolism , Animals , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/enzymology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/therapeutic use , Glucocorticoids/metabolism , Humans , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/therapeutic use , Metabolic Syndrome/drug therapy , Metabolic Syndrome/enzymology , Molecular Structure , Structure-Activity RelationshipABSTRACT
SCH 58261 is a reported adenosine A(2A) receptor antagonist which is active in rat in vivo models of Parkinson's 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 Parkinson's Disease, and has aqueous solubility of 100 microM at physiological pH.
Subject(s)
Adenosine A2 Receptor Antagonists , Chemistry, Pharmaceutical/methods , Parkinson Disease/drug therapy , Pyrimidines/chemical synthesis , Pyrimidines/pharmacokinetics , Triazoles/chemical synthesis , Triazoles/pharmacokinetics , Adenosine/chemistry , Administration, Oral , Animals , Area Under Curve , Disease Models, Animal , Drug Design , Hydrogen-Ion Concentration , Models, Chemical , Pyrimidines/chemistry , Rats , Solubility , Triazoles/chemistry , Water/chemistryABSTRACT
SCH 58261 is a reported adenosine A(2A) receptor antagonist, which is active in rat in vivo models of Parkinson's 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.
Subject(s)
Adenosine A2 Receptor Antagonists , Chemistry, Pharmaceutical/methods , Neuroprotective Agents/chemical synthesis , Neuroprotective Agents/pharmacology , Parkinson Disease/drug therapy , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Triazoles/chemical synthesis , Triazoles/pharmacology , Administration, Oral , Animals , Behavior, Animal/drug effects , Drug Design , Humans , Models, Chemical , Piperazines/chemistry , Quinolines/chemistry , Rats , Structure-Activity RelationshipABSTRACT
In search of a PDE5 inhibitor for erectile dysfunction, an SAR was developed from a PDE1/PDE5 purine series of leads, which had modest PDE5 potency and poor isozyme selectivity. A compound (41) with PDE5 inhibition and in vivo activity similar to sildenafil was discovered from this effort. In addition, purine 41 demonstrated superior overall PDE isozyme selectivity when compared to the approved PDE5 inhibitors sildenafil, vardenafil, and tadalafil, which may result in a more favorable side-effect profile.
Subject(s)
Erectile Dysfunction/drug therapy , Phosphodiesterase I/metabolism , Phosphodiesterase Inhibitors/chemical synthesis , Phosphodiesterase Inhibitors/therapeutic use , Phosphoric Diester Hydrolases/metabolism , Purines/chemical synthesis , Purines/therapeutic use , 3',5'-Cyclic-GMP Phosphodiesterases , Animals , Cyclic Nucleotide Phosphodiesterases, Type 5 , Humans , Male , Models, Molecular , Molecular Structure , Piperazines/pharmacology , Purines/chemistry , Rats , Sildenafil Citrate , Structure-Activity Relationship , Sulfones , Vasodilator Agents/chemical synthesis , Vasodilator Agents/pharmacology , Vasodilator Agents/therapeutic useABSTRACT
Development of structure-activity relationship of cyclic guanines I lead us to discovery of a potent and selective series of phosphodiesterase 5 inhibitors 52-59 (IC50=1.3-11.0 nM, PDE6/5=116-600).
Subject(s)
3',5'-Cyclic-GMP Phosphodiesterases/antagonists & inhibitors , Drug Delivery Systems/methods , Erectile Dysfunction/drug therapy , Erectile Dysfunction/enzymology , Guanine/chemistry , Phosphodiesterase Inhibitors/chemistry , 3',5'-Cyclic-GMP Phosphodiesterases/metabolism , Cyclic Nucleotide Phosphodiesterases, Type 5 , Guanine/administration & dosage , Humans , Male , Phosphodiesterase Inhibitors/administration & dosage , Phosphodiesterase Inhibitors/therapeutic use , Polycyclic Compounds/administration & dosage , Polycyclic Compounds/chemistry , Structure-Activity RelationshipABSTRACT
A wide range of neurotransmitters, polypeptides and inflammatory mediators transduce their signals into the interior of cell by specific interactions with cell-surface receptors that are coupled to G-protein. The most familiar G-protein-coupled receptors are muscarinic receptors, adrenergic receptors, dopaminergic receptors and opioid receptors. A single polypeptide chain of 400-500 residues forms most of these receptors. There are seven hydrophobic regions in the receptor and they correspond to transmembrane alpha-helices, which are membrane spanning domains. This topology is highly conserved among various members of the family of G-protein coupled receptors. The amino-terminal extracellular domain contains potential N-linked glycosylation sites in most receptors. The carboxyl-terminal is involved in the coupling to G-proteins and contains a cysteine site and phosphorylation site (Thr, Ser) and both are involved in receptor desensitization. In this section of the review we will discuss the development of potent, selective, low molecular weight antagonists of two G-protein coupled receptors (M(2) muscarinic receptor and CCR5 chemokine receptor) and their potential therapeutic utilities. The initial leads in both antagonist programs came from in house screening of our sample collections. As expected, most of the initial leads for both programs shared a similar pharmacophore and because of this showed strong affinity to many if not few a other G-protein coupled receptors. The initial significant challenge in both programs in terms of structure-activity studies was not only to optimize the structures for potency but also selectivity versus other subtype receptors. In the M(2) antagonist program the selectivity versus M(1) and other subtypes was a major challenge. Similarly in the CCR5 antagonist program the selectivity versus M(2) was a significant issue to overcome. In this review we will discuss in detail the structure activity relationships that resulted in potent and selective antagonists.
Subject(s)
CCR5 Receptor Antagonists , Muscarinic Antagonists/chemistry , Receptors, Muscarinic/metabolism , Animals , GTP-Binding Proteins/metabolism , Humans , Molecular Structure , Muscarinic Antagonists/pharmacology , Piperazine , Piperazines/chemistry , Piperazines/pharmacology , Piperidines/chemistry , Piperidines/pharmacology , Receptor, Muscarinic M2 , Signal Transduction/drug effects , Structure-Activity RelationshipABSTRACT
In search of a backup M(2) muscarinic receptor antagonist to the previously reported compound 1, we discovered compound (+)-14, which showed superior oral efficacy in animal models. The improvement of oral efficacy was achieved by modulating both the molecular weight and lipophilicity of the lead compounds.
Subject(s)
Autoreceptors/antagonists & inhibitors , Central Nervous System Agents/chemical synthesis , Muscarinic Antagonists/chemical synthesis , Piperidines/chemical synthesis , Receptors, Muscarinic/drug effects , Acetylcholine/metabolism , Administration, Oral , Animals , Avoidance Learning/drug effects , Central Nervous System Agents/chemistry , Central Nervous System Agents/pharmacology , Corpus Striatum/metabolism , Humans , In Vitro Techniques , Microdialysis , Molecular Conformation , Muscarinic Antagonists/chemistry , Muscarinic Antagonists/pharmacology , Piperidines/chemistry , Piperidines/pharmacology , Rats , Receptor, Muscarinic M2 , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
Benzamides/chemistry , Benzylidene Compounds/chemistry , Benzylidene Compounds/pharmacokinetics , Muscarinic Antagonists/chemistry , Muscarinic Antagonists/pharmacology , Receptors, Muscarinic/drug effects , Acetylcholine/analysis , Acetylcholine/biosynthesis , Animals , Area Under Curve , Benzamides/pharmacology , Drug Design , Drug Evaluation, Preclinical , Humans , Microdialysis , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Rats , Receptors, Muscarinic/metabolism , Structure-Activity RelationshipABSTRACT
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).
Subject(s)
Phosphodiesterase Inhibitors/chemical synthesis , Phosphodiesterase Inhibitors/pharmacology , Phosphoric Diester Hydrolases/metabolism , Xanthines/chemical synthesis , Xanthines/pharmacology , 3',5'-Cyclic-GMP Phosphodiesterases , Alkylation , Animals , Area Under Curve , Cyclic Nucleotide Phosphodiesterases, Type 5 , Drug Design , Electric Stimulation , In Vitro Techniques , Male , Muscle Contraction/drug effects , Muscle Relaxation/drug effects , Penis/drug effects , Piperazines/pharmacology , Purines , Rabbits , Sildenafil Citrate , Structure-Activity Relationship , SulfonesABSTRACT
Aryl carboxamides are useful structural units found in several biologically active compounds. Unlike their benzoic acid counterparts, fluorinated versions of naphthoic acids are relatively unknown. In connection with a recent project, we needed viable syntheses of several mono- and difluorinated naphthoic acids. Herein we describe the synthesis of 5-, 6-, 7-, and 8-fluoro-1-naphthalenecarboxylic acids and 5,7-, 5,8-, 6,7-, and 4,5-difluoro-1-naphthalenecarboxylic acids. The 5-fluoro derivative 1was obtained from the corresponding 5-bromo compound via electrophilic fluorination of the lithio-intermediate. The rest of the monofluoro (2, 3, and 4) and the difluoro acids (5, 6, and 7) were prepared by a new, general route which entailed the elaboration of commercial fluorinated phenylacetic acids to 2-(fluoroaryl)glutaric acids with differential ester groups; selective hydrolysis to a mono acid, intramolecular Friedel-Crafts cyclization, and aromatization furnished the target structures. An alternative process to assemble a naphthalene skeleton is also presented for the difluoro acids 5 and 6. Finally, 4,5-difluoro-1-naphthalenecarboxylic acid (8) was prepared expeditiously from 1,8-diaminonaphthalene by adapting classical reactions.