Design and synthesis of calindol derivatives as potent and selective calcium sensing receptor agonists.

We report the first comprehensive structure-activity study of calindol (4, (R)-N-[(1H-indol-2-yl)methyl]-1-(1-naphthyl)ethanamine), a positive allosteric modulator, or calcimimetic, of the calcium sensing receptor (CaSR). While replacement of the naphthyl moiety of calindol by other aromatic groups (phenyl, biphenyl) was largely detrimental to calcimimetic activity, incorporation of substituents on the 4, 5 or 7 position of the indole portion of calindol was found to provide either equipotent derivatives compared to calindol (e.g., 4-phenyl, 4-hydroxy, 5-hydroxycalindol 44, 52, 53) or, in the case of 7-nitrocalindol (51), a 6-fold more active calcimimetic displaying an EC50 of 20nM. Unlike calindol, the more active CaSR calcimimetics were shown not to act as antagonists of the closely related GPRC6A receptor, suggesting a more selective profile for these new analogues.

Design and synthesis of cyclic sulfonamides and sulfamates as new calcium sensing receptor agonists.

The design, synthesis and calcimimetic properties of various cyclic sulfonamides and sulfamates are described. The latter were prepared from the corresponding o-alkenylarenesulfonamides via copper- or rhodium-catalyzed intramolecular aziridination. The size of the cyclic sulfonamide rings as well as the position of the crucial (R)-naphthylethylamine substituent significantly affected calcimimetic activity. The most active compounds were the six- and seven-membered sulfonamides 30a and 31a and sulfamate 34a.

Diversity oriented syntheses of fused pyrimidines designed as potential antifolates.

Diversity oriented syntheses of some furo[2,3-d]pyrimidines and pyrrolo[2,3-d]pyrimidines related to folate, guanine, and diaminopyrimidine-containing drugs have been developed for the preparation of potential anti-infective and anticancer compounds. Amide couplings and Suzuki couplings on the basic heterocyclic templates were used, in the latter case yields being especially high using aromatic trifluoroborates as the coupling partner. A new ring synthesis of 6-aryl-substituted deazaguanines bearing 2-alkylthio groups has been developed using Michael addition of substituted nitrostyrenes. Diversity at C-2 has been introduced by oxidation and substitution with a range of amino nucleophiles. The chemical reactivity of these pyrrolopyrimidines with respect to both electrophilic substitution in ring synthesis and nucleophilic substitution for diversity is discussed. Several compounds were found to inhibit pteridine reductases from the protozoan parasites Trypanosoma brucei and Leishmania major at the micromolar level and to inhibit the growth of Trypanosma brucei brucei in cell culture at higher concentrations. From these results, significant structural features required for inhibition of this important drug target enzyme have been identified.

Two enantiomerically pure cyclic arenesulfonamide hydrochloride salts.

The crystal structures of N-[(1R)-1-(1-naphthyl)ethyl]-3,4-dihydro-2H-1,2-benzothiazin-4-aminium 1,1-dioxide chloride, C(20)H(21)N(2)O(2)S(+).Cl(-), (I), a six-membered cyclic sulfonamide, and (1R)-N-[(5,5-dioxo-6,7-dihydrodibenzo[d,f][1,2]thiazepin-7-yl)methyl]-1-(1-naphthyl)ethanaminium chloride, C(26)H(25)N(2)O(2)S(+).Cl(-), (II), a seven-membered cyclic sulfonamide, both representative of a novel family of agonists of the extracellular calcium sensing receptor (CaSR) of possible clinical importance, are reported. The known chirality of the naphthylethylamine precursor has enabled assignment of the absolute configuration of both compounds, which is crucial for the receptor recognition. The crystal structures, though different, reveal for these agonists a notable absence of intramolecular pi-pi stacking between their respective aromatic groups. This suggests a common structural feature that allows CaSR agonists to be distinguished from antagonists, since in the latter, such interactions have been shown to be important. The connectivities between molecules in the crystal structures are also different, but both involve hydrogen bonding mediated by chloride ions as a common dominant feature.

Novel calcium sensing receptor ligands: a patent survey.

INTRODUCTION: In the parathyroid gland, the calcium sensing receptor responds to small changes in circulating levels of Ca(2+), and consequently stimulates or inhibits the secretion of parathyroid hormone (PTH). Thus, ligands potentiating the action of calcium (calcimimetics) lead to decreased PTH secretion and can thus be useful for the treatment of hyperparathyroidism. On the other hand, ligands which antagonize the action of calcium (calcilytics) stimulate PTH secretion, favoring bone tissue regeneration. AREAS COVERED: This review first discusses the rapid development of calcimimetics (only one of which has been approved for the treatment of hyperparathyroidism) followed by that of calcilytics (none of which has as yet been approved for the treatment of osteoporosis). Peer-reviewed articles generated by these patents are also surveyed. EXPERT OPINION: The rapid progress in developing a clinically approved calcimimetic has not been matched by an identical success in finding an orally available calcilytic useful for the treatment of osteoporosis. However, the growing importance of osteoporosis as a debilitating disease is a stimulating factor in discovering such compounds.