ABSTRACT
A novel class of human ß(3)-adrenergic receptor agonists was designed in effort to improve selectivity and metabolic stability versus previous disclosed ß(3)-AR agonists. As observed, many of the ß(3)-AR agonists seem to need the acyclic ethanolamine core for agonist activity. We have synthesized derivatives that constrained this moiety by introduction of a pyrrolidine. This unique modification maintains human ß(3) functional potency with improved selectivity versus ancillary targets and also eliminates the possibility of the same oxidative metabolites formed from cleavage of the N-C bond of the ethanolamine. Compound 39 exhibited excellent functional ß(3) agonist potency across species with good pharmacokinetic properties in rat, dog, and rhesus monkeys. Early de-risking of this novel pyrrolidine core (44) via full AMES study supports further research into various new ß(3)-AR agonists containing the pyrrolidine moiety.
Subject(s)
Adrenergic beta-Agonists/chemistry , Adrenergic beta-Agonists/pharmacology , Pyrrolidines/chemistry , Receptors, Adrenergic, beta-3/drug effects , Crystallography, X-Ray , Drug Discovery , Humans , Models, MolecularABSTRACT
We report herein the discovery of benzodiazepine sulfonamide-based bombesin receptor subtype 3 (BRS-3) agonists and their unusual chirality. Starting from a high-throughput screening lead, we prepared a series of BRS-3 agonists with improved potency and pharmacokinetic properties, of which compound 8a caused mechanism-based, dose-dependent food intake reduction and body weight loss after oral dosing in diet-induced obese mice. This effort also led to the discovery of a novel family of chiral molecules originated from the conformationally constrained seven-membered diazepine ring.
ABSTRACT
Design, synthesis, and SAR of a series of 3H-spiro[isobenzofuran-1,4'-piperidine] based compounds as potent, selective and orally bioavailable melanocortin subtype-4 receptor (MC4R) agonists are disclosed.
Subject(s)
Piperidines/chemistry , Receptor, Melanocortin, Type 4/agonists , Administration, Oral , Animals , Brain/metabolism , Crystallography, X-Ray , Drug Evaluation, Preclinical , Humans , Molecular Conformation , Piperidines/chemical synthesis , Piperidines/pharmacology , Rats , Rats, Sprague-Dawley , Receptor, Melanocortin, Type 4/metabolism , Spiro Compounds/chemistry , Structure-Activity RelationshipABSTRACT
This paper describes the discovery of N-[(4R)-6-(4-chlorophenyl)-7-(2,4-dichlorophenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-yl]-5-methyl-1H-pyrazole-3-carboxamide (MK-5596, 12c) as a novel cannabinoid-1 receptor (CB1R) inverse agonist for the treatment of obesity. Structure-activity relationship (SAR) studies of lead compound 3, which had off-target hERG (human ether-a-go-go related gene) inhibition activity, led to the identification of several compounds that not only had attenuated hERG inhibition activity but also were subject to glucuronidation in vitro providing the potential for multiple metabolic clearance pathways. Among them, pyrazole 12c was found to be a highly selective CB1R inverse agonist that reduced body weight and food intake in a DIO (diet-induced obese) rat model through a CB1R-mediated mechanism. Although 12c was a substrate of P-glycoprotein (P-gp) transporter, its high in vivo efficacy in rodents, good pharmacokinetic properties in preclinical species, good safety margins, and its potential for a balanced metabolism profile in man allowed for the further evaluation of this compound in the clinic.
Subject(s)
Anti-Obesity Agents/chemical synthesis , Pyrans/chemical synthesis , Pyridines/chemical synthesis , Receptor, Cannabinoid, CB1/antagonists & inhibitors , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Animals , Anti-Obesity Agents/pharmacokinetics , Anti-Obesity Agents/pharmacology , Binding, Competitive , Body Weight/drug effects , Cell Line , Cricetinae , Cricetulus , Crystallography, X-Ray , Dogs , Drug Inverse Agonism , Eating/drug effects , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , Glucuronides/metabolism , Haplorhini , Hepatocytes/metabolism , Humans , Mice , Mice, Knockout , Models, Molecular , Molecular Conformation , Pyrans/pharmacokinetics , Pyrans/pharmacology , Pyridines/pharmacokinetics , Pyridines/pharmacology , Rats , Receptor, Cannabinoid, CB1/genetics , Stereoisomerism , Structure-Activity RelationshipABSTRACT
We report the design, synthesis and properties of spiroindane based compound 1, a potent, selective, orally bioavailable, non-peptide melanocortin subtype-4 receptor agonist. Compound 1 shows excellent erectogenic activity in the rodent models.
Subject(s)
Erectile Dysfunction/drug therapy , Indans/chemistry , Indans/therapeutic use , Receptor, Melanocortin, Type 4/agonists , Receptor, Melanocortin, Type 4/metabolism , Spiro Compounds/chemistry , Spiro Compounds/therapeutic use , Animals , CHO Cells , Cricetinae , Cricetulus , Dogs , Haplorhini , Humans , Indans/pharmacokinetics , Indans/pharmacology , Male , Mice , Molecular Structure , Protein Binding , Rats , Spiro Compounds/pharmacokinetics , Spiro Compounds/pharmacology , Structure-Activity RelationshipABSTRACT
Azaindole based structures were evaluated as DP1 receptor antagonists. This work has lead to the discovery of potent, selective and distinct DP1 receptor antagonists.
Subject(s)
Prostaglandin Antagonists/chemical synthesis , Receptors, Prostaglandin/antagonists & inhibitors , Humans , Indoles/chemical synthesis , Indoles/chemistry , Indoles/pharmacology , Prostaglandin Antagonists/pharmacology , Receptors, Prostaglandin/physiology , Structure-Activity RelationshipABSTRACT
A novel series of 1-sulfonyl-4-acylpiperazines as selective cannabinoid-1 receptor (CB1R) inverse agonists was discovered through high throughput screening (HTS) and medicinal chemistry lead optimization. Potency and in vivo properties were systematically optimized to afford orally bioavailable, highly efficacious, and selective CB1R inverse agonists that caused food intake suppression and body weight reduction in diet-induced obese rats and dogs. It was found that the receptor binding assay predicted in vivo efficacy better than functional antagonist/inverse agonist activities. This observation expedited the structure-activity relationship (SAR) analysis and may have implications beyond the series of compounds presented herein.
Subject(s)
Anti-Obesity Agents/chemical synthesis , Piperazines/chemical synthesis , Receptor, Cannabinoid, CB1/antagonists & inhibitors , Sulfonamides/chemical synthesis , Animals , Anti-Obesity Agents/chemistry , Anti-Obesity Agents/pharmacology , Biological Availability , Body Weight/drug effects , Dogs , Drug Inverse Agonism , Eating/drug effects , Hepatocytes/metabolism , Humans , In Vitro Techniques , Macaca mulatta , Microsomes, Liver/metabolism , Models, Molecular , Piperazines/chemistry , Piperazines/pharmacology , Rats , Stereoisomerism , Structure-Activity Relationship , Sulfonamides/chemistry , Sulfonamides/pharmacologyABSTRACT
The reactions of chiral benzyl carbocations bearing alpha-phenyl substituents with N-sulfonylated indoles afford 1,1,2-triarylalkanes with anti-selectivities. This outcome is a reversal of facial diastereoselectivity relative to Bach's alpha-alkyl-bearing benzyl cations. The reactions are promoted by either a Brønsted acid (TFA) or Lewis acid (BF3.OEt2), offering differential diastereoselectivities and reactivities. The electronic properties of both reacting partners strongly influence the reaction rates and the product diastereoselectivities and appear to operate under kinetic control. This chemistry provides an efficient access to sterically congested tetrasubstituted ethanes.
Subject(s)
Alkanes/chemical synthesis , Indoles/chemistry , Alkanes/chemistry , Alkylation , Benzene Derivatives/chemistry , Catalysis , Combinatorial Chemistry Techniques , Molecular Structure , StereoisomerismABSTRACT
The Candida albicans Fitness Test, a whole-cell screening platform, was used to profile crude fermentation extracts for novel antifungal natural products with interesting mechanisms of action. An extract with intrinsic antifungal activity from the fungus Fusarium larvarum displayed a Fitness Test profile that strongly implicated mRNA processing as the molecular target responsible for inhibition of fungal growth. Isolation of the active components from this sample identified a novel class of isoxazolidinone-containing natural products, which we have named parnafungins. These natural products were isolated as an interconverting mixture of four structural- and stereoisomers. The isomerization of the parnafungins was due to a retro-Michael ring-opening and subsequent reformation of a xanthone ring system. This interconversion was blocked by methylation of an enol moiety. Structure elucidation of purified parnafungin derivatives was accomplished by X-ray crystallography and NMR analysis. The biochemical target of these natural products has been identified as the fungal polyadenosine polymerase. Parnafungins demonstrated broad spectrum antifungal activity with no observed activity against gram-positive or gram-negative bacteria. The intact isoxazolidinone ring was required for antifungal activity. In addition, the natural products were efficacious in a mouse model of disseminated candidiasis.
Subject(s)
Antifungal Agents/isolation & purification , Fusarium/chemistry , Oxazolidinones/isolation & purification , Antifungal Agents/chemistry , Antifungal Agents/pharmacology , Candida albicans/drug effects , Crystallography, X-Ray , Microbial Sensitivity Tests , Models, Molecular , Nuclear Magnetic Resonance, Biomolecular , Oxazolidinones/chemistry , Oxazolidinones/pharmacology , Spectrometry, Mass, Electrospray Ionization , Spectrophotometry, Infrared , Spectrophotometry, UltravioletABSTRACT
X-ray crystallographic, NMR spectroscopic, and computational studies of taranabant afforded similar low-energy conformers with a significant degree of rigidity along the C11-N13-C14-C16-C17 backbone but with more flexibility around bonds C8-C11 and C8-O7. Mutagenesis and docking studies suggested that taranabant and rimonabant shared the same general binding area of CB1R but with significant differences in detailed interactions. Similar to rimonabant, taranabant interacted with a cluster of aromatic residues (F(3.36)200, W(5.43)279, W(6.48)356, and Y(5.39)275) through the two phenyl rings and with F(2.57)170 and L(7.42)387 through the CF 3-Pyr ring. The notable distinction between taranabant and rimonabant was that taranabant was hydrogen-bonded with S(7.39)383 but not with K(3.28)192, while rimonabant was hydrogen-bonded with K(3.28)192 but not with S(7.39)383. The strong hydrogen bonding between the amide NH of taranabant and hydroxyl of S(7.39)383 was key to the superior affinity of taranabant to CB1R.
Subject(s)
Amides/chemistry , Amides/pharmacology , Pyridines/chemistry , Pyridines/pharmacology , Receptor, Cannabinoid, CB1/agonists , Amino Acid Sequence , Animals , Binding Sites , CHO Cells , Cells, Cultured , Computer Simulation , Cricetinae , Cricetulus , Crystallography, X-Ray , Humans , Hydrogen Bonding , Magnetic Resonance Spectroscopy/methods , Magnetic Resonance Spectroscopy/standards , Models, Molecular , Molecular Conformation , Molecular Sequence Data , Molecular Structure , Mutagenesis, Site-Directed , Receptor, Cannabinoid, CB1/chemistry , Receptor, Cannabinoid, CB1/genetics , Reference Standards , Sequence Alignment , Structure-Activity RelationshipABSTRACT
A new series of indole-based antagonists of the PGD(2) receptor subtype 1 (DP1 receptor) was identified and the progress of the structure-activity relationship study to the identification of potent and selective antagonists is presented. Selective DP1 antagonists with high potency and selectivity were prepared. Of particular interest is the DP1 antagonist 26 with a K(i) value of 1 nM for the DP1 receptor and an IC(50) value of 4.6 nM in a DP1 functional assay for the inhibition of the PGD(2) induced cAMP production in platelet rich plasma (PRP).
Subject(s)
Hydrogen/chemistry , Indoles/chemical synthesis , Indoles/pharmacology , Pyridines/chemistry , Receptors, Immunologic/antagonists & inhibitors , Receptors, Immunologic/metabolism , Receptors, Prostaglandin/antagonists & inhibitors , Receptors, Prostaglandin/metabolism , Blood Platelets/drug effects , Blood Platelets/metabolism , Humans , Indoles/chemistry , Molecular Structure , Stereoisomerism , Structure-Activity RelationshipABSTRACT
In an effort to shed light on the active binding conformation of our 3-amino-1-alkyl-cyclopentane carboxamide CCR2 antagonists, we prepared several conformationally constrained analogs resulting from backbone cyclization. Evaluation of CCR2 binding affinities for these analogs gave insight into the optimal relative positions of the piperidine and benzylamide moieties while simultaneously leading to the discovery of a new, potent lead type based upon a spirocyclic acetal scaffold.
Subject(s)
Cyclopentanes/chemistry , Receptors, CCR2/antagonists & inhibitors , Spiro Compounds/chemistry , Acetals/chemistry , Acetals/pharmacology , Crystallography, X-Ray , Cyclopentanes/pharmacology , Humans , Kinetics , Molecular Conformation , Monocytes/drug effects , Monocytes/metabolism , Receptors, CCR2/metabolism , Spiro Compounds/pharmacology , Structure-Activity RelationshipABSTRACT
SAR studies on amides, ureas, and vinylogous amides derived from pyrrolidine led to the discovery of several potent hNK(1) antagonists. One particular vinylogous amide (45b) had excellent potency, selectivity, pharmacokinetic profile, and functional activity in vivo. An in vivo rhesus macaque brain receptor occupancy PET study for compound 45b revealed an estimated Occ(90) approximately 300 ng/ml.
Subject(s)
Neurokinin-1 Receptor Antagonists , Pyrrolidines/pharmacology , Administration, Oral , Animals , Biological Availability , Brain/metabolism , Humans , Macaca mulatta , Pyrrolidines/pharmacokinetics , Species SpecificityABSTRACT
The discovery of the potent and selective prostaglandin D2 (PGD2) receptor (DP) antagonist [(3R)-4-(4-chlorobenzyl)-7-fluoro-5-(methylsulfonyl)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl]-acetic acid (13) is presented. Initial lead antagonists 6 and 7 were found to be potent and selective DP antagonists (DP Ki = 2.0 nM for each); however, they both suffered from poor pharmacokinetic profiles, short half-lives and high clearance rates in rats. Rat bile duct cannulation studies revealed that high concentrations of parent drug were present in the biliary fluid (Cmax = 1100 microM for 6 and 3900 microM for 7). This pharmacokinetic liability was circumvented by replacing the 7-methylsulfone substituent present in 6 and 7 with a fluorine atom resulting in antagonists with diminished propensity for biliary excretion and with superior pharmacokinetic profiles. Further optimization led to the discovery of the potent and selective DP antagonist 13.
Subject(s)
Indoles/chemical synthesis , Receptors, Immunologic/antagonists & inhibitors , Receptors, Prostaglandin/antagonists & inhibitors , Airway Obstruction/drug therapy , Animals , Bile/metabolism , Binding, Competitive , Dogs , Hepatocytes/metabolism , Humans , In Vitro Techniques , Indoles/pharmacokinetics , Indoles/pharmacology , Macaca fascicularis , Male , Mice , Microsomes/metabolism , Nasal Decongestants/chemical synthesis , Nasal Decongestants/pharmacokinetics , Nasal Decongestants/pharmacology , Protein Binding , Rats , Rats, Sprague-Dawley , Sheep , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A 1,6-naphthyridine inhibitor of HIV-1 integrase has been discovered with excellent inhibitory activity in cells, good pharmacokinetics, and an excellent ability to inhibit virus with mutant enzyme.
Subject(s)
HIV Integrase Inhibitors/chemical synthesis , HIV Integrase Inhibitors/pharmacokinetics , Naphthyridines/chemical synthesis , Administration, Oral , Animals , Cells, Cultured , HIV Integrase/drug effects , HIV Integrase/genetics , HIV Integrase Inhibitors/pharmacology , Humans , Inhibitory Concentration 50 , Mutation , Naphthyridines/pharmacokinetics , Naphthyridines/pharmacology , Rats , Structure-Activity RelationshipABSTRACT
Fatty acids are essential for survival of bacteria and are synthesized by a series of enzymes including the elongation enzymes, beta-ketoacyl acyl carrier protein synthase I/II (FabF/B). Inhibition of fatty acid synthesis is one of the new targets for the discovery and development of antibacterial agents. Platensimycin (1a) is a novel broad spectrum Gram-positive antibiotic produced by Streptomyces platensis. It was discovered by target-based whole-cell screening strategy using antisense differential sensitivity assay. It inhibits bacterial growth by selectively inhibiting condensing enzyme FabF of the fatty acid synthesis pathway and was isolated by a two-step process, a capture step followed by reversed-phase HPLC. The structure was elucidated by 2D NMR methods and confirmed by X-ray crystallographic analysis of a bromo derivative. It was determined that potential reactivity of the enone moiety does not play a key role in the biological activity of platensimycin. However, cyclohexenone ring conformation renders for the stronger binding interaction with the enzyme. The isolation, structure elucidation, derivatization, and biological activity of 6,7-dihydroplatensimycin are described.
Subject(s)
Adamantane/chemistry , Aminobenzoates/chemistry , Anilides/chemistry , Anti-Bacterial Agents/chemistry , Streptomyces/chemistry , Adamantane/isolation & purification , Adamantane/pharmacology , Aminobenzoates/isolation & purification , Aminobenzoates/pharmacology , Anilides/isolation & purification , Anilides/pharmacology , Anti-Bacterial Agents/isolation & purification , Anti-Bacterial Agents/pharmacology , Crystallography, X-Ray , Models, Molecular , Molecular Conformation , Nuclear Magnetic Resonance, Biomolecular , StereoisomerismSubject(s)
Antipsychotic Agents/chemistry , Antipsychotic Agents/pharmacology , Benzamides/chemistry , Drug Design , Glycine Plasma Membrane Transport Proteins/antagonists & inhibitors , Sulfonamides/chemistry , Animals , Antipsychotic Agents/chemical synthesis , Mice , Mice, Inbred DBA , Rats , Schizophrenia/drug therapy , Structure-Activity RelationshipABSTRACT
The synthesis and optimization of a cyclopentane-based hNK1 antagonist scaffold 3, having four chiral centers, will be discussed in the context of its enhanced water solubility properties relative to the marketed anti-emetic hNK1 antagonist EMEND (Aprepitant). Sub-nanomolar hNK1 binding was achieved and oral activity comparable to Aprepitant in two in vivo models will be described.
Subject(s)
Cyclopentanes/chemistry , Cyclopentanes/pharmacology , Neurokinin-1 Receptor Antagonists , Water , Administration, Oral , Animals , CHO Cells , Cricetinae , Cyclopentanes/adverse effects , Cyclopentanes/chemical synthesis , Humans , Molecular Structure , Receptors, Neurokinin-1/genetics , Receptors, Neurokinin-1/metabolism , Solubility , Structure-Activity RelationshipABSTRACT
A novel indole series of PGD2 receptor (DP receptor) antagonists is presented. Optimization of this series led to the identification of potent and selective DP receptor antagonists. In particular, antagonists 35 and 36 were identified with Ki values of 2.6 and 1.8 nM, respectively. These two antagonists are also potent in a DP functional assay where they inhibit the PGD2 induced cAMP production in platelet rich plasma with IC50 values of 7.9 and 8.6 nM, respectively. The structure-activity relationships of this indole series of DP receptor antagonists will also be discussed.
Subject(s)
Indoles/chemistry , Indoles/pharmacology , Receptors, Immunologic/antagonists & inhibitors , Receptors, Prostaglandin/antagonists & inhibitors , Indoles/chemical synthesis , Molecular Structure , Receptors, Immunologic/metabolism , Receptors, Prostaglandin/metabolism , Safrole/analogs & derivatives , Safrole/chemistry , Structure-Activity RelationshipABSTRACT
[reaction: see text] The chemical behavior of 1,2-bis-triisopropylsilanylsulfanyl alkenes 1 is relatively unexplored, and the weak sulfur-silicon bonds give rise to various transformations. Under acidic conditions (HCl) and in the presence of a Lewis acid at room temperature the bicyclic adduct 2 is obtained in good yield. The structure was confirmed by X-ray crystal analysis with R = benzyl.