BOOMSLANG: a program for combinatorial structure generation.

An approach to exploiting pharmacophore models is described. Structures are assembled combinatorially from user-defined fragments and flexibly overlaid into the reference frame of the pharmacophore using distance geometry and molecular mechanics. The match with the pharmacophore is quantified by conformational energy and volume of overlap.

Pharmacophoric pattern matching in files of three-dimensional chemical structures: implementation of flexible searching.

The conformational space of a flexible three-dimensional (3D) molecule can be represented for searching purposes by a smoothed bounded distance matrix. Such matrices provide an effective way of carrying out flexible searching, but search times can be very long when compared with rigid searches that take no account of conformational flexibility. This paper considers two techniques for minimizing the computational requirements of flexible searching. In the first part, we compare four different indices that have been suggested for the quantification of molecular flexibility, and demonstrate that they produce comparable rankings of sets of molecules in order of decreasing flexibility. We then demonstrate that the prioritization of a set of structures in order of increasing flexibility can result in substantial reductions in the time requirements of flexible searching if some fixed number of hit structures is desired. In the second part, we report an analysis of the 3D crystal structures in the Cambridge Structural Database to generate distance ranges that are tighter than those produced by distance geometry. Experiments with a set of six query pharmacophores demonstrate that use of these tightened ranges results in substantial reductions in search times, but that this may also lead to a reduction in the number of hit molecules obtained from the final conformational search.

New nonpeptide angiotensin II receptor antagonists. 3. Synthesis, biological properties, and structure-activity relationships of 2-alkyl-4-(biphenylylmethoxy)pyridine derivatives.

A novel series of nonpeptide angiotensin II (AII) receptor antagonists is reported, derived from linkage of the biphenylyltetrazole moiety found in previously described antagonists via a methyleneoxy chain to the 4-position of a 3-substituted 2,6-dialkylpyridine. When evaluated in an in vitro binding assay using a guinea pig adrenal membrane preparation, compounds in this series generally gave IC50 values in the range 0.005-0.5 microM. A variety of substituents was found to be effective at the 3-position of the pyridine ring. On intravenous administration in a normotensive rat model, the more potent compounds inhibited the AII-induced pressor response with ED50 values in the range 0.1-1.0 mg/kg. One of the compounds, 2-ethyl-5,6,7,8-tetrahydro-4-([2'-(1H-tetrazol-5-yl)biphenyl-4y l] methoxy)quinoline (26), demonstrated good oral activity in two rat models. At doses in the range 1-10 mg/kg po in AII-infused, conscious, normotensive rats, the compound exhibited a dose-related inhibition of the pressor response with a good duration of action at the higher doses. In a renal hypertensive rat model compound 26 showed a rapid and sustained lowering of blood pressure at a dose of 5 mg/kg po. Based on its profile, this compound, designated ICI D6888, has been selected for evaluation in volunteers.

Pharmacophoric pattern matching in files of three-dimensional chemical structures: use of bounded distance matrices for the representation and searching of conformationally flexible molecules.

This paper discusses the use of bounded distance matrices for the representation of conformationally flexible three-dimensional (3D) molecules. It is shown that pharmacophoric pattern searches of databases of flexible 3D molecules represented in this way can be carried out using screen and geometric searching algorithms that are analogous to those used for searching databases of rigid 3D structures. Molecules matching a query pattern after the geometric search must then undergo a final conformational search to determine whether they can, in fact, adopt a conformation that matches the query. An analysis of this three-stage searching procedure shows that searching databases of flexible 3D molecules is extremely demanding of computational resources.

The aminoquinazoline group as a replacement for the salicylamide group: the design and synthesis of a novel highly selective beta 1 adrenoceptor partial agonist.

The high potency at beta 1 receptors, excellent selectivity (beta 1/beta 2) and high degree of agonism displayed by compounds such as 1 is believed to be due in part to the salicylamide side chain. Two conformations of salicylamide are known to exist in the crystal state (2 and 3), but ab initio calculations suggest that in the absence of crystal packing forces 2 should be more stable. The aminoquinazoline group was judged to be a good replacement for salicylamide in 1, and consequently the oxypropanolamine derivative 4 was prepared. 4 shows extremely high potency at the beta 1 receptor, and excellent beta 1/beta 2 selectivity. It has comparable in vitro activity to 1, although it displays a lower degree of agonism. These results suggest that in this system aminoquinazoline appears to be an excellent mimic of the salicylamide group.

Pharmacophoric pattern matching in files of three-dimensional chemical structures: use of smoothed bounded distances for incompletely specified query patterns.

This paper describes a technique for increasing the screen-out of pharmacophoric pattern searches in the databases of three-dimensional chemical structures when only some of the interatomic distances in the query pattern are specified. The technique involves the application of a distance bounds-smoothing procedure to the query distances; this smoothing allows the calculation of upper and lower bounds for the unspecified distances. The bounded distances can then be used to set screens additional to those that are set to describe the distances that have been specified by the searcher. Evidence is presented to suggest that use of the technique can lead to increases in the efficiency of substructure searches for partially specified query patterns.