Silicon switches of marketed drugs.

The application of organosilicon chemistry is a strategy to develop best in class drugs applied to targets that have been validated as tractable and drug-able. Silicon switches of known drugs have been synthesised and evaluated in biological assay systems then compared to their marketed all-carbon counterparts. Recent examples include the silicon switches of drugs haloperidol, fexofenadine, bexarotene and venlafaxine.

Design strategies for building drug-like chemical libraries.

There has been increased pressure over the last few years to design and synthesize chemical libraries that are more 'drug-like' in character. This review discusses what 'drug-like' is assumed to be, then examines recent developments in the prediction of 'drug-likeness'. It is noted that, while many methods allow a scientist to identify 'non-drug-like' molecules with a reasonable degree of certainty, a need still exists for physically meaningful descriptors that allow a chemist to design in 'drug-likeness', rather than relying on a computer to screen out unsuitable compounds.

4-Hydroxy-1-[3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl]piperidines: selective h5-HT1D agonists for the treatment of migraine.

A series of 4-hydroxy-1-[3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl] piperidines was investigated as potential selective h5-HT1D agonists for the treatment of migraine. The 4-[(N-benzyl-N-methyl)amino]methyl analog 12a was found to be a full agonist at the h5-HT1D receptor with good binding selectivity over the h5-HT1B receptor.

Substituted pyrazoles as novel selective ligands for the human dopamine D4 receptor.

Two novel series of 3-(heterocyclylmethyl)pyrazoles have been synthesised and evaluated as ligands for the human dopamine D4 receptor. Compounds in series I (exemplified by 8k) have a phenyl ring joined to the 4-position of the pyrazole while those in series II (exemplified by 15j) have a 5-phenyl ring linked by a saturated chain to the 4-position of the pyrazole. Both series supplied compounds with excellent affinity for the human D4 and good selectivity over other dopamine receptors. Excellent selectivity over calcium, sodium, and potassium ion channels was also achieved.

Binding of 2,4-disubstituted morpholines at human D4 dopamine receptors.

The synthesis of a series of 2,4-disubstituted morpholines is described and their affinities at human dopamine receptors reported. The orally bioavailable 7-azaindole compound 11 has nanomolar affinity at the hD4 receptor with > 1000-fold selectivity over the hD2 receptor.

L-687,306: a functionally selective and potent muscarinic M1 receptor agonist.

The oxadiazole L-687,306 is a high affinity muscarinic agonist with a N-methylscopolamine/oxotremorine-M binding profile predictive of a partial agonist. L-687,306 showed marked selectivity in functional pharmacological assays. L-687,306 was a partial agonist at muscarinic M1 receptors in the rat ganglion but a high affinity competitive antagonist at guinea-pig cardiac M2 and ileal M3 muscarinic receptors. This compound gives an opportunity to study receptor reserve involved in muscarinic receptors in vitro and in vivo.

Synthesis and in vitro biological profile of all four isomers of the potent muscarinic agonist 3-(3-methyl-1,2,4-oxadiazol-5-yl)-1-azabicyclo[2.2.1]heptane.

The four stereoisomers of the muscarinic agonist 7 have been synthesized from enantiomerically pure exo-azanorbornane esters (13a,b). The esters were obtained in optically active form by separation of the carboxamide diastereomers 12a,b, formed from the borane complex of exo-azanorbornane-3-carboxylate 10 and a chiral amine auxiliary. Using the known chirality of (R)-alpha-methylbenzylamine, an X-ray analysis was accomplished on 12a in order to determine the absolute configuration of the azanorbornane C4 chiral center. Each of the chiral esters 13a,b was separately transformed into the oxadiazoles with concomitant epimerization at C3 of the azanorbornane ring to afford the thermodynamic equilibrium mixture of isomers. Chromatographic separation followed by analysis of each isomer by NMR and GC allowed the absolute stereochemistry of all four isomers of 7 to be confirmed. Full biological evaluation in biochemical and pharmacological assays revealed that the 3R,4R isomer was the most active on receptor binding studies and the most potent on the pharmacological preparations, showing a 50-fold increase in potency at the M2 and M3 sites compared to M1.

Tetrahydropyridyloxadiazoles: semirigid muscarinic ligands.

Recent studies have described novel azabicycle-based muscarinic agonists which readily penetrate into the central nervous system and are capable of displaying high efficacy at cortical sites. The current paper describes the synthesis and biochemical assessment of semirigid muscarinic ligands which were used to map the requirements of the cortical muscarinic receptor and to study the degree of conformational flexibility required to cause receptor activation. Analogues 6 and 9 provide high-efficacy muscarinic agonists at cortical sites; however, C-alkylation on the tetrahydropyridine ring resulted in more rigid analogues and showed lower predicted efficacy. Molecular mechanics calculations indicated a preference for the E rotameric form. This conformation was also observed in the X-ray crystal structure of ethenyloxadiazole 12. The new compounds were tested in a biochemical assay designed to measure receptor affinity and to predict cortical efficacy.

Synthesis and biological activity of 1,2,4-oxadiazole derivatives: highly potent and efficacious agonists for cortical muscarinic receptors.

The synthesis and biochemical evaluation of novel 1,2,4-oxadiazole-based muscarinic agonists which can readily penetrate into the CNS is reported. Efficacy and binding of these compounds are markedly influenced by the structure and physicochemical properties of the cationic head group. In a series of azabicyclic ligands efficacy and affinity are influenced by the size of the surface area presented to the receptor, at the active site, and the degree of conformational flexibility. The exo-1-azanorbornane 16a represents the optimum arrangement, and this compound is one of the most efficacious and potent muscarinic agonists known. In a series of isoquinuclidine based muscarinic agonists efficacy and affinity are influenced by the geometry between the cationic head.group and hydrogen bond acceptor pharmacophore and steric bulk in the vicinity of the base. The anti configuration represented by 22a is optimal for muscarinic activity. Ligands with pKa below 6.5 show poor binding to the muscarinic receptor as exemplified by the diazabicyclic derivative 42.

Selective thyromimetics. Cardiac-sparing thyroid hormone analogues containing 3'-arylmethyl substituents.

Introduction of specific arylmethyl groups at the 3'-position of the thyroid hormone 3,3',5-triiodo-L-thyronine (T3), and its known hormonally active derivatives, gives liver-selective, cardiac-sparing thyromimetics, with potential utility as plasma cholesterol lowering agents. Selectivity-conferring 3'-substituents include substituted benzyl, e.g. p-hydroxybenzyl, and heterocyclic methyl, e.g. 2-oxo-1,2-dihydropyrid-5-ylmethyl and 6-oxo-1,6-dihydropyridazin-3-ylmethyl. Correlations between in vivo and in vitro receptor binding affinities show that liver/heart selectivity does not depend on receptor recognition but on penetration or access to receptors in vivo. QSAR studies of the binding data of a series of 20 3'-arylmethyl T3 analogues show that electronegative groups at the para position increase both receptor binding and selectivity in vivo. However, increasing 3'-arylmethyl hydrophobicity increases receptor binding but reduces selectivity. Substitution at ortho and meta positions reduces both binding and selectivity. Replacement of the 3,5-iodo groups by halogen or methyl maintains selectivity, with 3,5-dibromo analogues in particular having increased potency combined with oral bioavailability. Diphenyl thioether derivatives also have improved potency but are less orally active. At the 1-position, the D enantiomer retains selectivity, but removal of the alpha-amino group to give a propionic acid results in loss of selective thyromimetic activity.

2-Methyl-1,3-dioxaazaspiro[4.5]decanes as novel muscarinic cholinergic agonists.

Many nonquaternary ammonium muscarinic agonists have been developed over the last few years, but most of the existing compounds (e.g., arecoline, RS-86, AF-30) behave as weak partial agonists at cholinergic receptors in tissues of limited receptor reserve. The current paper describes the synthesis and biochemical assessment of analogues of AF-30 designed to have sufficient conformational freedom to allow greater receptor flexibility and hence activation. The new compounds and important standards were tested in a new biochemical assay designed to measure both receptor affinity and intrinsic activity of each compound and for their ability to stimulate phosphatidylinositol turnover in rat cerebral cortex. Two azaspirodecanes (5a and 5b) were shown to have far greater predicted efficacy than AF-30.

Thyroid hormone analogues. Synthesis of 3'-substituted 3,5-diiodo-L-thyronines and quantitative structure-activity studies of in vitro and in vivo thyromimetic activities in rat liver and heart.

Twenty-nine novel 3'-substituted derivatives of the thyroid hormone 3,3',5-triiodo-L-thyronine (T3) have been synthesized by using established methods and by a new route involving manipulation of a 3'-formyl intermediate. In vitro hormone receptor binding (to intact nuclei) and in vivo thyromimetic activity (induction of mitochondrial 3-phosphoglycerate oxidoreductase, GPDH) were measured in rat liver and heart for these new analogues and for the 18 previously reported 3'-substituted 3,5-diiodo-L-thyronines. Analysis of the binding data using theoretical conformational and quantitative structure-affinity methods implies that the 3'-substituent recognition site on the thyroid hormone receptor is hydrophobic and limited in depth to the length of the natural iodo substituent, but has sufficient width to accommodate a phenyl or cyclohexyl group. Receptor binding is reduced by approximately 10-fold in 3'-acyl derivatives which form strong intramolecular acceptor hydrogen bonds with the adjacent 4'-hydroxyl. The compounds studied showed no differences in their relative affinities for heart and liver nuclei, suggesting that receptors in these tissues are similar. However, the relationships between thyromimetic activity (induction of GPDH) and nuclear binding showed some tissue differences. A high correlation between activity and binding is observed for full agonists in the heart, but an equally significant correlation for the liver data is only seen when 3'-substituent bulk (molar refractivity) is included in the analysis. These results suggest the possibility that differential tissue penetration or access to receptors may occur in vivo.

Synthesis and characterization of all four isomers of the muscarinic agonist 2'-methylspiro[1-azabicyclo[2.2.2]octane-3,4'-[1,3]dioxolane].

The four separated isomers of the muscarinic agonist 1, previously known as AF30, have been synthesized by a route that has allowed the absolute stereochemistry of each isomer to be assigned. With the chirality of (-)-camphanic acid known, X-ray analysis of the more crystalline intermediate diastereomeric camphanate 5A allowed the absolute stereochemistry at the quinuclidine chiral center to be determined. Each diastereomer was separately transformed into the spirodioxolane with concomitant introduction of the second chiral center. Chromatographic separation followed by a second crystal structure determination revealed the absolute stereochemistry of all four isomers of 1. Detailed biological evaluation of each isomer indicated that while the 3(R),2'(S) isomer was the most active in binding studies, it was the 3(R),2'(R) isomer that displayed the largest functional selectivity between ganglion (M-1 site) and heart (M-2 site). With the same internal chiral standard, the absolute configuration of the more active enantiomer of 3 was shown to be S, confirming earlier literature reports.

Synthesis and antihypertensive activity of 6,7-disubstituted trans-4-amino-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ols.

A series of novel 6,7-disubstituted trans-3,4-dihydro-2, 2-dimethyl-4-pyrrolidino-(or piperidino)-2H-1-benzopyran-3-ols was prepared and tested for antihypertensive activity in the conscious spontaneously hypertensive rat (SHR) and compared with certain of their monosubstituted analogues. The potent blood pressure lowering activity of the 6-monosubstituted compounds was enhanced by incorporation of an acetylamino or amino group at C(7) and that of the 7-nitro-substituted compound by incorporation of an amino (but not an acetylamino group) at C(6). The combination of 6-nitro or 6-cyano with 7-(acetylamino) or 7-amino groups and 6-amino with 7-nitro groups in trans-4-pyrrolidino- or -4-piperidino-2,2-dimethyl-2H-1-benzopyranols conferred superior antihypertensive activity to hydralazine and to the calcium antagonist, nifedipine, in SHR. The synthetic route to these compounds involves the conversion of 2H-1-benzopyrans to bromohydrins that were treated with pyrrolidine or piperidine. Preparation of the 6-cyano-7-amino analogue was accomplished when 6-cyano-7-[(trifluoroacetyl)amino]-2,2-dimethylbenzopyran was used as starting material.