Past approaches to discovering new medicines

A brief account is given of the main approaches to new drug discovery which have been taken during the twentieth century. Four main sources for new drugs are described and each of these is discussed in turn; they are: natural products, existing drugs, screens and physiological transmitters.Se hace una breve historia de las principales aproximaciones al descubrimiento de nuevos fármacos. Se describen cuatro de las principales aproximaciones: productos naturales, uso de prototipos existentes, screening farmacológico y transmisores fisiológicos

Aproximaciones históricas al descubrimiento de nuevos fármacos

Se hace una breve historia de las principales aproximaciones al descubrimiento de nuevos fármacos. Se describen cuatro de las principales aproximaciones: productos naturales, uso de prototipos existentes, screening farmacológico y transmisores fisiológicos.A brief account is given of the main approaches to new drug discovery which have been taken during the twentieth century. Four main sources for new drugs are described and each of these is discussed in turn; they are: natural products, existing drugs, screens and physiological transmitters

Structure - activity studies with histamine H3 - receptor ligands

Analogues of thioperamide have been synthesised and tested in vitro on rat cerebral cortex to explore structure-activity relationships with the intention of designing compounds which do not possess the thiourea group of thioperamide and which may have improved brain penetration. Compounds derived from histamine and having an aromatic nitrogencontaining heterocyc1e on the side-chain amino group have been found to act as H3 - antagonists. These have served as leads to provide aryloxyethyl- and aryloxypropylimidazoles which are potent H3 antagonists of histamine. Structure-activity relationships for agonists are brief1y reviewed. Analogues of the very potent and selective agonist, imetit (S-[2-imidazol-4-yl)ethyl]isothiourea) have been studied to explore the transition between agonist, partial agonist and antagonist. The isosteric isourea is also a potent agonist. N,N' -Dibutyl-[S-[3-(imidazol-4-yl)propyl]isothiourea is a very potent antagonist having K¡=1.5 nM.Se han sintetizado análogos de tioperamida. Los compuestos han sido ensayados in vitro para explorar los factores que permitan diseñar compuestos derivados de la tioperamida sin grupo tiourea que mejoren la penetración cerebral. Los compuestos más activos como H3-antagonistas contienen un átomo de nitrógeno aromático hetorocíclico sobre la cadena lateral. Estos compuestos se han empleado como cabeza de serie para obtener potentes H3-antagonistas de histarnina con estructura de ariloxietil y ariloxipropilimidazoles. Las relaciones estructura actividad de agonistas se han revisado brevemente. Se han estudiado un grupo de análogos de (S-[2-imidazol-4-il)etil]isotiourea (imetit) con el objeto de explorar la transición entre agonistas y antagonistas. N,N' -dibutil-[S-[3-(imidazol- 4-il)propil]isotiourea es un muy potente antagonistas que tiene Ki=1.5 nM

r-2,c-6-Bis(4-fluoro­phen­yl)-t-3,t-5-dimethyl­piperidin-4-one

In the title compound, C19H19F2NO, the piperidinone ring adopts a chair conformation. The crystal packing is stabilized by C—H⋯O and C—H⋯F inter­molecular inter­actions, generating centrosymmetric dimers of R 2 2(14) and R 2 2(24) rings

Imidazolium 3-nitro­benzoate

In the title compound, C3H5N2 +·C7H4NO4 −, the benzene ring forms a dihedral angle of 40.60 (5)° with the imidizolium ring. The nitro­benzoate anion is approximately planar: the benzene ring makes dihedral angles of 3.8 (3) and 3.2 (1)° with the nitro and carboxyl­ate groups, respectively. In the crystal structure, the cations and anions are linked by inter­molecular N—H⋯O hydrogen bonds, forming a zigzag chain along the b axis

1-[2,4,6-Trimethyl-3,5-bis­(4-oxopiperidin-1-ylmeth­yl)benz­yl]piperidin-4-one

In the structure of the title compound, C27H39N3O3, each of the (4-oxopiperidin-1-yl)methyl residues adopts a flattened chair conformation (with the N and carbonyl groups being oriented to either side of the central C4 plane) and they occupy positions approximately orthogonal to the central benzene ring [Cbenzene—C—Cmethyl­ene—N torsion angles 103.4 (2), −104.4 (3) and 71.9 (3)°]; further, two of these residues are oriented to one side of the central benzene ring with the third to the other side. In the crystal packing, supra­molecular layers in the ab plane are sustained by C—H⋯O inter­actions

Structure - activity studies with histamine H3 - receptor ligands

Se han sintetizado análogos de tioperamida. Los compuestos han sido ensayados in vitro para explorar los factores que permitan diseñar compuestos derivados de la tioperamida sin grupo tiourea que mejoren la penetración cerebral. Los compuestos más activos como H3-antagonistas contienen un átomo de nitrógeno aromático hetorocíclico sobre la cadena lateral. Estos compuestos se han empleado como cabeza de serie para obtener potentes H3-antagonistas de histarnina con estructura de ariloxietil y ariloxipropilimidazoles. Las relaciones estructura actividad de agonistas se han revisado brevemente. Se han estudiado un grupo de análogos de (S-[2-imidazol-4-il)etil]isotiourea (imetit) con el objeto de explorar la transición entre agonistas y antagonistas. N,N' -dibutil-[S-[3-(imidazol- 4-il)propil]isotiourea es un muy potente antagonistas que tiene Ki=1.5 nM.Analogues of thioperamide have been synthesised and tested in vitro on rat cerebral cortex to explore structure-activity relationships with the intention of designing compounds which do not possess the thiourea group of thioperamide and which may have improved brain penetration. Compounds derived from histamine and having an aromatic nitrogen containing heterocyc1e on the side-chain amino group have been found to act as H3 - antagonists. These have served as leads to provide aryloxyethyl- and aryloxypropylimidazoles which are potent H3 antagonists of histamine. Structure-activity relationships for agonists are brief1y reviewed. Analogues of the very potent and selective agonist, imetit (S-[2-imidazol-4-yl)ethyl]isothiourea) have been studied to explore the transition between agonist, partial agonist and antagonist. The isosteric isourea is also a potent agonist. N,N' -Dibutyl-[S-[3-(imidazol-4-yl)propyl]isothiourea is a very potent antagonist having K¡=1.5 nM

5′′-(4-Chloro­benzyl­idene)-4′-(4-chloro­phen­yl)-5-fluoro-1′,1′′-dimethyl­indoline-3-spiro-2′-pyrrolidine-3′-spiro-3′′-piperidine-2,4′′-dione

The piperidine ring of the title compound, C30H26Cl2FN3O2, adopts a twisted chair conformation. The pyrrolidine ring has a twisted envelope structure with the N atom at the flap [displaced by 0.592 (3) Å]. The fluoro­oxindole, chloro­phenyl and chloro­benzyl­idene groups are planar with r.m.s. deviations of 0.0348, 0.0048 and 0.0048 Å, respectively. The structure is stabilized by inter­molecular N—H⋯O hydrogen bonds

1-Chloro­acetyl-3-isopropyl-r-2,c-6-diphenyl­piperidin-4-one

In the title compound, C22H24ClNO2, the piperidine ring adopts a distorted boat conformation. The dihedral angle between the two phenyl rings is 83.2 (1)°. In the crystal, the mol­ecules are linked into chains running along the b axis by C—H⋯O hydrogen bonds. The Cl atom of the chloro­acetyl group is disordered over two positions with occupancies of 0.66 (2) and 0.34 (2)

Histamine receptor activation by unsaturated (allyl and propargyl) homologs of histamine

The spectrum of agonist activity for three new homologs of histamine (cis- and trans-imidazolylallylamine and imidazolylpropargylamine) was evaluated in the isolated guinea pig ileum and right atrium. The homologs were about three log units less potent than histamine in stimulating contractions of the longitudinal muscles of the ileum, but they were histamine-like, pharmacologically, because they were sensitive to blockade by pyrilamine and resistant to blockade by atropine. In the right atrium, these weak agonists were partially sensitive to blockade by cimetidine. The agonist activity of the cis-isomer in particular was completely blocked by a combination of cimetidine and propranolol, but resistant to reserpine treatment (neuronal catecholamine depletion). Therefore, these homologs of histamine have the ability to stimulate H 1 - and H 2 -histamine receptors and beta -adrenoreceptors in vitro .Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44880/1/11_2005_Article_BF01966582.pd