ABSTRACT
The inhibition of aldosterone synthase (CYP11B2) may be an effective treatment of hypertension and heart failure, among other ailments. Previously reported benzimidazole CYP11B2 inhibitors led the way for bioisosteric imidazopyridines that are both potent and selective over CYP11B1.
Subject(s)
Cytochrome P-450 CYP11B2/antagonists & inhibitors , Imidazoles/pharmacology , Pyridines/pharmacology , Animals , Cricetulus , Humans , Imidazoles/chemical synthesis , Imidazoles/chemistry , Imidazoles/pharmacokinetics , Macaca mulatta , Male , Microsomes, Liver/metabolism , Pyridines/chemical synthesis , Pyridines/chemistry , Pyridines/pharmacokinetics , Rats, Wistar , Steroid 11-beta-Hydroxylase/antagonists & inhibitors , Structure-Activity RelationshipABSTRACT
Bombesin receptor subtype-3 (BRS-3) is an orphan G-protein coupled receptor belonging to the subfamily of bombesin-like receptors. BRS-3 is implicated in the development of obesity and diabetes. We report here small-molecule agonists that are based on a 4-(alkylamino)pyridine-3-sulfonamide core. We describe the discovery of 2a, which has mid-nanomolar potency, selectivity for human BRS-3 versus the other bombesin-like receptors, and good bioavailability.
Subject(s)
Pyridines/chemistry , Receptors, Bombesin/agonists , Sulfonamides/pharmacology , Sulfonylurea Compounds/pharmacology , Animals , Biological Availability , Hydrogen Bonding , Male , Rats , Rats, Sprague-Dawley , Sulfonamides/chemistry , Sulfonamides/pharmacokinetics , Sulfonylurea Compounds/chemistry , Sulfonylurea Compounds/pharmacokineticsABSTRACT
We report the development and characterization of compound 22 (MK-5046), a potent, selective small molecule agonist of BRS-3 (bombesin receptor subtype-3). In pharmacological testing using diet-induced obese mice, compound 22 caused mechanism-based, dose-dependent reductions in food intake and body weight.
ABSTRACT
Multiple X-ray crystallographic and 1H NMR spectroscopic studies demonstrate that 2,6-disubstituted aryl groups exert a strong effect on acyclic conformation, inducing the geminal and vicinal hydrogens on the adjacent sp3-sp3 C-C bond to adopt an antiperiplanar orientation. Twenty-one examples comprising nitrile, ketone, and dithiane aldols are provided. A search of the Cambridge Structural Database uncovered an additional 11 examples of this effect. This preference causes some unanticipated remote effects on acyclic conformations: in anti-nitrile aldols, this effect causes 2,6-disubstituted aryls to generally prefer a gauche, rather than antiperiplanar, relationship to the largest vicinal groups. X-ray crystallography, 1H-1H NOESY spectroscopy, and computation demonstrate that minimization of allylic 1,3-strain and syn-pentane-like interactions work together in establishing this conformational preference.
Subject(s)
Pharmaceutical Preparations/chemical synthesis , Phenazines/chemical synthesis , Spiro Compounds/chemical synthesis , Steroids/chemical synthesis , Vinblastine/chemical synthesis , Antineoplastic Agents, Phytogenic/chemistry , Molecular Structure , Pharmaceutical Preparations/chemistry , Phenazines/chemistry , Spiro Compounds/chemistry , Steroids/chemistry , Vinblastine/chemistryABSTRACT
A collection of structurally complex and chemically diverse small molecules is a useful tool to explore cell circuitry. In this article, we report the split-pool synthesis of more than 3000 spirooxindoles on high capacity macrobeads. The key reaction to assemble the spirooxindole core stereoselectively is a Lewis acid variant of the Williams' three-component coupling. After formation, the skeleton was elaborated using Sonogashira couplings, amide forming reactions, and N-acylations of gamma-lactams. The final library was analyzed by sampling individual macrobeads and by using binomial confidence limits. It was determined that at least 82% of the library compounds should have better than 80% purity. To demonstrate the utility of our discovery process, a high-throughput chemical genetic modifier screen was performed using stock solutions of the resultant products. A number of positives were identified as enhancers of the cellular actions of latrunculin B, an actin polymerization inhibitor. Through resynthesis, we confirmed one of the positives and demonstrated that, in yeast cells, it has an EC50 in the sub-micromolar range.
Subject(s)
Indoles/chemical synthesis , Spiro Compounds/chemical synthesis , Aldehydes/chemistry , Alkynes/chemistry , Combinatorial Chemistry Techniques/methods , Lactams/chemistry , Magnetic Resonance Spectroscopy/methods , StereoisomerismABSTRACT
As a consequence of the wide-ranging significance of beta-lactams (e.g., use as drugs and as chiral building blocks), a great deal of effort has been dedicated to the development of methods for their stereoselective synthesis. Although considerable progress has been achieved, nearly all of the approaches that have been described are based on the use of chiral precursors; direct catalytic enantioselective routes to beta-lactams are rare as well as limited in scope. In this communication, we establish that, using a new C2-symmetric planar-chiral bis(azaferrocene) ligand, we can generate beta-lactams with very good enantiomeric excess and cis diastereoselection via catalytic enantioselective Kinugasa reactions (couplings of alkynes with nitrones). Appealing attributes of this process include the ready availability of the starting materials, the functional-group tolerance of the reaction, and the convergency of the approach.
