reaction: see text 2-4-(tert-Butoxycarbonyl)piperazinylbenzylidene-tert-butanesulfinamides underwent nucleophilic 1,2-addition with different organometallic reagents to give highly diastereomerically ...enriched adducts. X-ray crystallography of the resulting alpha-branched N-Boc-2-piperazinylbenzyl-tert-butanesulfinamides confirms different mechanisms depending on the organometallic reagent used. Differential deprotection of the N-Boc and the tert-butanesulfinamides was investigated, and the dehydration byproducts have been identified and characterized. To avoid the formation of byproducts in the acidic deprotection step, the N-tert-butanesulfinamide group was converted to the corresponding N-tert-butanesulfonamide (Bus), which allowed for clean orthogonal deprotection. The efficient synthesis and deprotection of the N-Boc-2-piperazinylbenzyl-tert-butanesulfinamides herein described constitutes an attractive method for extensive structure-activity studies in the search for novel ligands of the human melanocortin 4 receptor.
Benzylamine and pyridinemethylamine derivatives were synthesized and characterized as potent and selective antagonists of the melanocortin-4 receptor (MC4R). These compounds were also profiled in ...rodents for their pharmacokinetic properties. Two compounds with diversified profiles in chemical structure, pharmacological activities, and pharmacokinetics, 10 and 12b, showed efficacy in an established murine cachexia model. For example, 12b had a K i value of 3.4 nM at MC4R, was more than 200-fold selective over MC3R, and had a good pharmacokinetic profile in mice, including high brain penetration. Moreover, 12b was able to stimulate food intake in the tumor-bearing mice and reverse their lean body mass loss. Our results provided further evidence that a potent and selective MC4R antagonist with appropriate pharmacokinetic properties might potentially be useful for the treatment of cancer cachexia.
Structure–activity relationship studies were conducted to reduce CYP2D6-mediated metabolism in a series of indene H₁-antihistamines. Reductions in pKₐ via incorporation of a β-fluoro substituent or a ...heteroaryl moiety were shown to reduce contributions to metabolism through this pathway. Several compounds, including 8l, 8o, and 12f were identified with promising primary in vitro profiles and reduced biotransformation via CYP2D6.
Analogs of the known H(1)-antihistamine R-dimethindene with suitable selectivity for key GPCRs, P450 enzymes and hERG channel were assessed for metabolism profile and in vivo properties. Several ...analogs were determined to exhibit diverse metabolism. One of these compounds, 10a, showed equivalent efficacy in a rat EEG/EMG model to a previously identified clinical candidate and a potentially superior pharmacokinetic profile as determined from a human microdose study.
The melanocortin-4 receptor (MC4R) plays an important role in the regulation of energy homeostasis. Recent studies have shown that blockade of the MC4R reverses tumor-induced weight loss in mice. ...Herein, we describe the synthesis and identification of potent and selective non-peptide antagonists of the human MC4R from a series of 2-ethoxycarbonylcyclohexyl-piperazines. Compound
12i was found to possess low nanomolar affinity for the MC4R, and exhibit oral bioavailability in rats. More importantly, when administered orally to mice (10
mg/kg), it led to statistically significant increases in food intake over a 24-h period.
Self-Folding Cavitands of Nanoscale Dimensions Lücking, Ulrich; Tucci, Fabio C; Rudkevich, Dmitry M ...
Journal of the American Chemical Society,
09/2000, Letnik:
122, Številka:
37
Journal Article
Recenzirano
New types of resorcinarene-based nanoscale container molecules 2 and 3 are described. They feature reversibly folding unimolecular cavities of nanoscale dimensions and ∼800 Å3 internal volume; they ...are among the largest synthetic unimolecular hosts prepared to date. Two seams of intramolecular hydrogen bonds, provided by 12 secondary amides, control the guest uptake and release. The hydrogen bonds resist the unfolding of the host and increase the energetic barrier to guest exchange. Exchange is slow on the NMR time scale (room temperature), and kinetically stable complexes result. The direct observation of bound species and the stoichiometry of the complexes are reported. A series of adamantyl and cyclohexyl guests 11 − 19 of various shapes and lengths were prepared and used to estimate the hosts' capacities. Compound 2 exists in an S-shaped conformation and its two cavities act independently; each half of host 2 formed kinetically stable complexes with either two identical or different guest molecules. The C-shaped host 3 accommodates rigid and long guests with association constants (K a) between 500 ± 50 M-1 (−ΔG 295 = 3.6 ± 0.1 kcal mol-1) and 270 ± 100 M-1 (−ΔG 295 = 3.2 ± 0.2 kcal mol-1) for adamantyl derivatives. With the more flexible and/or shorter guests, fast exchange between the free and complexed guest species was observed at room and higher temperatures (in toluene-d 8). Guest exchange rates of the new hosts are considerably faster than rates seen with typical hemicarceplexes but slower than those of other open-ended cavitands.
Recent studies have demonstrated that melanocortin-4 receptor (MC4R) antagonists can prevent weight loss in tumor-bearing mice, which indicates clinical usage for the treatment of cachexia. In our ...efforts to develop potent and selective antagonists of the human MC4R, we designed piperazinebenzylamines bearing a 2,4-dichlorophenylalanine, by utilizing information derived from structure−activity relationships of MC4R agonists and mutagenesis results of the MC4R and peptide ligands. On the basis of known MC4R agonists such 6, we successfully synthesized potent MC4R antagonists exemplified by 10, which possesses a K i value of 1.8 nM in binding affinity. 10 does not stimulate cAMP release in HEK 293 cells expressing the human MC4 receptor at 10 μM concentration. It was demonstrated by Schild analysis that 10 was a competitive functional antagonist with a pA 2 value of 7.9 in the inhibition of α-MSH-stimulated cAMP accumulation. 10 also penetrated into the brain when dosed intravenously in rats.
Further structure−activity relationship studies of a series of substituted uracils at the 1, 3, and 5 positions resulted in the discovery of several potent antagonists of the human ...gonadotropin-releasing hormone receptor. Uracils bearing a side chain derived from phenylglycinol at the 3-position were shown to be orally bioavailable in monkeys. 3-(2R)-Amino-2-phenylethyl-1-(2,6-difluorobenzyl)-5-(2-fluoro-3-methoxyphenyl)-6-methylpyrimidin-2,4-dione (R-13b, NBI 42902) displayed subnanomolar binding affinity (K i = 0.56 nM) and was a potent functional antagonist (IC50 = 3.0 nM in Ca2+ flux assay) at the human GnRH receptor. It also bound to the monkey GnRH receptor with high affinity (K i = 3.9 nM). In addition, R-13b had good plasma exposure in cynomolgus monkeys after oral administration, with a C max of 737 ng/mL and an AUC of 2392 ng/mL·h at a 10 mg/kg dose. Moreover, oral administration of R-13b to castrated male cynomolgus monkeys resulted in a significant decrease in serum levels of luteinizing hormone. These results demonstrate that compounds from this series of uracils are potent GnRH antagonists with good oral bioavailability and efficacy in nonhuman primates.
A series of pyrrolidine derivatives were synthesized and characterized as potent agonists of the human melanocortin-4 receptor. For example,
28c had a
K
i of 13
nM in binding affinity and EC
50 of ...6.9
nM in agonist potency with an intrinsic activity of 100% of the endogenous ligand α-MSH.
Cavitands with self-complementary shapes (3 and 4) were prepared by the covalent attachment of adamantane guest molecules to the upper rim of the host structures. Relatives of the “self-folding” ...cavitands 2, these new structures possess a seam of intramolecular hydrogen bonds that stabilize the folded conformation. Their self-complementary shapes result in the formation of noncovalent dimers of considerable kinetic and thermodynamic stability (−ΔG 295 = 4.5 kcal/mol for 3a and 6.5 kcal/mol for 4a in p-xylene-d 10). The dimerization of cavitands 3 and 4 is reversible and subject to control by solvent and temperature. The dimerization process is enthalpically favored and entropy opposed and occurs with significant enthalpy−entropy compensation.
