Cyclic amine sulfonamides as linkers in the design and synthesis of novel human beta(3) adrenergic receptor agonists

Piperidine, pyrrolidine, and azetidine sulfonamides were examined as linkers in designing novel human beta(3) adrenergic receptor (beta(3)-AR) agonists. The azetidine derivative 37, and piperidine derivatives 7, 8, and 13 were found to be potent beta(3)-AR agonists and have good selectivity against beta(1)- and beta(2)-AR.     

Regulation of the rainbow trout (Oncorhynchus mykiss) hepatic beta2-adrenoceptor by adrenergic agonists

The characteristics of hepatic beta(2)-adrenoceptors (AR) were examined in rainbow trout (Oncorhynchus mykiss) chased once per day to exhaustion for up to 7 days or fed the repartitioning agents clenbuterol (CLEN) or ractopamine (RACT) that function in mammals as beta-agonists. A one-day chase and feeding the CLEN for 37 days resulted in a significant 27% and 33% decrease, respectively, in the number of CGP-binding sites (B(max)) with no significant change in affinity (Kd) of hepatic beta(2)-ARs. Despite the significant decrease in beta(2)-AR numbers with CLEN feeding, no significant differences were found for either beta(2)-AR mRNA levels or adenylyl cyclase (ACase) activities. In addition, CLEN displayed only partial agonist activities as it was found to be more effective at blocking isoproterenol-stimulated cAMP production in isolated hepatocytes than stimulating cAMP production. The small affects of RACT may be related to its low active stereoisomer content and low affinity for the trout beta(2)-AR. Agonist regulation of the trout hepatic beta(2)-ARs may involve down-regulation of the receptors without affecting responsiveness.     

Discovery of novel steroidal histamine H3 receptor antagonists/inverse agonists

Emerging from an HTS campaign, novel steroid-based histamine H₃ receptor antagonists were identified and characterized. Structural moieties of the hit compounds were combined to improve binding affinities which resulted in compound 4 as lead molecule. During the lead optimization due to the versatile modifications of diamino steroid derivatives, several in vitro potent compounds with subnanomolar binding affinities to histamine H₃ receptors were found. The unfavorable binding to rat muscarinic receptors was successfully reduced by tuning the basicity. Compound 20 showed significant in vivo activity in the rat dipsogenia model and could serve as a pharmacological tool in the future.     

Potent benzimidazolone based human beta(3)-adrenergic receptor agonists

The synthesis and biological evaluation of a series of benzimidazolone beta(3) adrenergic receptor agonists are described. A trend toward the reduction of rat atrial tachycardia upon increasing steric bulk at the 3-position of the benzimidazolone moiety was observed.     

Stereospecific synthesis of (-)-neplanocin F

The stereospecific synthesis of (-)-neplanocin F was achieved in 15 steps from 2,3-O-isopropylidene-D-1,4-ribonolactone. The synthetic methodology can give an access through appropriate modifications to new series of carbanucleosides.     

Tricyclic pharmacophore-based molecules as novel integrin alpha(v)beta3 antagonists. Part 2: synthesis of potent alpha(v)beta3/alpha(IIb)beta3 dual antagonists

We synthesized 4-aminopiperidine derivatives of our prototype integrin alpha(v)beta3 antagonist 1 in an attempt to increase the activity and water solubility. Introduction of one or two hydrophilic moieties into the central aromatic ring and/or the benzene ring at the C-terminus of 1 increased water solubility and enhanced inhibition of cell adhesion. The results of a structure-activity relationships (SAR) study indicated that the torsion angle between the central aromatic ring and the piperidine ring, and the acidity at the sulfonamide moiety, might be important for alpha(v)beta3 receptor binding activity. Some of these compounds are novel and potent alpha(v)beta3/alpha(IIb)beta3 dual antagonists with acceptable water solubility and a satisfactory early absorption, distribution, metabolism, excretion, and toxicity (ADMET) profile.     

Co-crystal structure guided array synthesis of PPARgamma inverse agonists

PPARgamma-activating thiazolidinediones and carboxylic acids such as farglitazar exert their anti-diabetic effects in part in PPARgamma rich adipose. Both pro- and anti-adipogenic PPARgamma ligands promote glucose and lipid lowering in animal models of diabetes. Herein, we disclose representatives of an array of 160 farglitazar analogues with atypical inverse agonism of PPARgamma in mature adipocytes.     

Thienopyrimidines as β3-adrenoceptor agonists: Hit-to-lead optimization

Resulting from a vHTS based on a pharmacophore alignment on known β3-adrenoceptor ligands, an aryloxypropanolamine scaffold comprising a thienopyrimidine moiety was further optimized as a human β3-AR agonist, yielding a lead compound with an excellent cellular activity of EC₅₀ = 20 pM, selectivity over hβ1- and hβ2-adrenoceptors and a promising safety profile.     

Stereospecific synthesis of a novel series of pyridine nucleosides

Condensation of $\text{3,5-}\text{di}\text{-O-}\text{benzoyl}\text{-β-}\text{d}\text{-}\text{ribofuranosyl}$ chloride severally with 3-acetyl-5-alkylpyridines, 5-alkyl-3-methoxycarbonylpyridines (alkyl = Me, Et, Pr, and ⁱPr), 5-isopropylnicotinamide, and 3,5-diacetylpyridine bis(ethylene acetal) in acetonitrile at ?5° gave the corresponding $\text{1-(3,5-}\text{di}\text{-O-}\text{benzoyl}\text{-β-}\text{d}\text{-}\text{ribofuranosyl}\text{))-3,5-}\text{disubstituted}$ pyridinium chlorides in excellent yield (90%). From the reaction of a series of $\text{2,3-O-}\text{isopropylidene}\text{-β-}\text{d}\text{-ribofuranosyl}$ halides with 3-acetyl-5-methyl-pyridine at room temperature, the α-nucleosides were obtained.     

Stereospecific synthesis of 3 beta-hydroxylated bile alcohols

This paper describes the synthesis of 5 beta-cholestane-3 beta, 7 alpha,25-triol and 5 beta-cholestane-3 beta, 7 alpha, 12 alpha, 25-tetrol from their corresponding 3 alpha-analogs. The method consists of refluxing a mixture of a steroid alcohol, triphenylphosphine, and diethyl azodicarboxylate in benzene solution with an acid such as formic acid. The sterically pure ester (3 beta-formate) so formed after saponification then allows an easy access to the epimer of the starting alcohol. Differentiation of these 3 beta-hydroxy bile alcohols from their corresponding 3 alpha-epimeric analogs was made possible on the basis of proton, 13C-NMR, and mass spectra as well as chromatographic mobility. Steric requirements of sterols and nucleophilicity of attacking acidic components played an important role for the success of this synthesis. Only equatorial hydroxyl groups in these bile alcohols reacted under mild conditions and epimerization, as well as protection of the alcoholic group, was achieved in one step. Formic acid was the acid of choice since the axial formate ester formed is sufficiently reactive to be hydrolyzed (KHCO3/aq X MeOH) under mild conditions.     

Design, synthesis, and biological evaluation of novel 7-azaindolyl-heteroaryl-maleimides as potent and selective glycogen synthase kinase-3beta (GSK-3beta) inhibitors

Two approaches were developed to synthesize the novel 7-azaindolyl-heteroarylmaleimides. The first approach was based upon the palladium-catalyzed Suzuki cross-coupling or Stille cross-coupling of 2-chloro-maleimide 5 with various arylboronic acids or arylstannanes. The second approach was based upon the condensation of ethyl 7-azaindolyl-3-glyoxylate 12 with various acetamides. The hydroxypropyl-substituted 7-azaindolylmaleimide template was first used to screen different heteroaryls attached to the maleimide. Replacement of hydroxypropyl with different chain lengths and different functional groups were studied next. Many compounds synthesized were demonstrated to have high potency at GSK-3beta, good GS activity in HEK293 cells and good to excellent metabolic stability in human liver microsomes. Three representative compounds (21, 33, and 34) were demonstrated to have good selectivity against a panel of 80 kinase assays. Among them, compound 33 exhibited very weak inhibitions at the other 79 kinase assays, and behaved as a highly selective GSK-3beta inhibitor.     

Tricyclic pharmacophore-based molecules as novel integrin alpha(v)beta3 antagonists. Part 1: design and synthesis of a lead compound exhibiting alpha(v)beta3/alpha(IIb)beta3 dual antagonistic activity

In order to generate novel compounds with integrin alpha(v)beta3-antagonistic activity together with antiplatelet activity, tricyclic pharmacophore-based molecules were designed and synthesized. Although piperazine-containing compounds initially prepared were selective alpha(IIb)beta3 antagonists, replacement of piperazine with piperidine furnished a potent alpha(v)beta3/alpha(IIb)beta3 dual antagonist. Structure-activity relationship (SAR) studies provided clues for further development of tricyclic pharmacophore-based integrin antagonists.     

Tricyclic pharmacophore-based molecules as novel integrin alpha(v)beta3 antagonists. Part III: synthesis of potent antagonists with alpha(v)beta3/alpha(IIb)beta3 dual activity and improved water solubility

In order to optimize our novel integrin alpha(v)beta3/alpha(IIb)beta3 dual antagonists, spatial screening at the N-terminus was performed. The alpha(v)beta3 antagonistic activity varied depending on the space that was occupied by the N-terminus, but high potency against alpha(IIb)beta3 was well maintained. The (3S)-aminopiperidine analogue had the strongest activity against alpha(v)beta3, and the S isomer at piperidine was more potent than the R isomer. Compounds selected on the basis of SAR analysis of a novel lead compound showed acceptable early absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiles and sufficient water solubility for use as infusion drugs. Docking studies with the alpha(v)beta3 receptor were performed to confirm the SAR findings.     

Design and synthesis of novel tetra-peptide motilin agonists

A series of novel tetra-peptide motilin agonists, having the general structure H-Phe-Val-X-Ile-NH(2), were designed, on the basis of structure-activity relationship studies of motilin. Peptides, in which X is a side chain substituted tryptophan residue, have agonistic activity. H-Phe-Val-Trp(2'-CH(2)CH(2)OH)-Ile-NH(2)(7), H-Phe-Val-Trp(2'-SCH(3))-Ile-NH(2)(8), and H-Phe-Val-Trp(2'-SCH(2)CH(2)CH(3))-Ile-NH(2)(9), showed an EC(50) for contractile activity in the rabbit smooth muscle of 14.1+/-3.2, 12.9+/-4.1, and 4.6+/-1.6 microM, respectively. Interaction of the tryptophan aliphatic side chain with motilin receptor appears to influence the signal transduction via motilin receptor.     

Development of novel 2-[4-(aminoalkoxy)phenyl]-4(3H)-quinazolinone derivatives as potent and selective histamine H3 receptor inverse agonists

Novel 2-[4-(aminoalkoxy)phenyl]-4(3H)-quinazolinone derivatives were identified as potent human H(3) receptor inverse agonists. After systematic modification of lead 5a, the potent and selective analog 5r was identified. Elimination of hERG K(+) channel and human alpha(1A)-adrenoceptor activities is the main focus of the present study.     

Novel (4-piperidin-1-yl)-phenyl sulfonamides as potent and selective human beta(3) agonists

A series of novel (4-piperidin-1-yl)-phenyl sulfonamides was prepared and evaluated for their biological activity on the human beta(3)-adrenergic receptor (AR). Replacement of the 3,4-dihydroxyl group of the catechol moiety with 4-hydroxyl-3-methyl sulfonamide on the left-hand side of the compounds resulted in a number of potent full agonists at the beta(3) receptor. Modification of the right-hand side of the compounds by incorporation of a free carboxylic acid resulted in a few potent human beta(3) agonists with low affinities for beta(1)- and beta(2)-ARs. N-Alkyl substitution on the 4-piperidin-1-yl-phenylamine further increased the beta(3) potency while maintaining the selectivity. For example, sulfonamide 48 is a potent full beta(3) agonist (EC(50)=0.004 microM, IA=1.0) with > 500-fold selectivity over beta(1)- and beta(2)-ARs.     

Design and synthesis of novel 3-hydroxy-cyclobut-3-ene-1,2-dione derivatives as thyroid hormone receptor beta (TR-beta) selective ligands

Design and synthesis of a novel 3-hydroxy-cyclobut-3-ene-1,2-dione derivatives are reported and their in vitro thyroid hormone receptor selectivity has been evaluated in the thyroid luciferase receptor assay. The 3-[3,5-dichloro-4-(4-hydroxy-3-isopropylphenoxy)-phenylamino]-4-hydroxy-cyclobut-3-ene-1,2-dione 21 has shown selectivity towards thyroid hormone receptor β.     

Substituted phenoxypropyl-(R)-2-methylpyrrolidine aminomethyl ketones as histamine-3 receptor inverse agonists

Optimization of a series of aminomethyl ketone diamine H(3)R antagonists to reduce the brain exposure by lowering the pKa, led to molecules with improved pharmacokinetic properties. Compounds 9, 19, and 25 had high affinity for human H(3)R and demonstrated in vivo H(3)R functional activity in the rat dipsogenia model. Compound 9 displayed modest wake-promoting activity in the rat EEG/EMG model.     

Beta(1)/beta(2)/beta(3)-adrenoceptor knockout mice are obese and cold-sensitive but have normal lipolytic responses to fasting

Catecholamines are viewed as major stimulants of diet- and cold-induced thermogenesis and of fasting-induced lipolysis, through the β-adrenoceptors (β₁/β₂/β₃). To test this hypothesis, we generated β₁/β₂/β₃-adrenoceptor triple knockout (TKO) mice and compared them to wild type animals. TKO mice exhibited normophagic obesity and cold-intolerance. Their brown fat had impaired morphology and lacked responses to cold of uncoupling protein-1 expression. In contrast, TKO mice had higher circulating levels of free fatty acids and glycerol at basal and fasted states, suggesting enhanced lipolysis. Hence, β-adrenergic signalling is essential for the resistance to obesity and cold, but not for the lipolytic response to fasting.