Discovery of potent cyclic GMP phosphodiesterase inhibitors. 2-Pyridyl- and 2-imidazolylquinazolines possessing cyclic GMP phosphodiesterase and thromboxane synthesis inhibitory activities.

Moderate cyclic GMP phosphodiesterase (cGMP-PDE, PDE V) inhibitor 2-phenyl-4-anilino-quinazoline (1) was identified utilizing MultiCASE assisted drug design (MCADD) technology. Modification of compound 1 was conducted at the 2-, 4-, and 6-positions of the quinazoline ring for enhancement of cGMP-PDE inhibitory activity. The 6-substituted 2-(imidazol-1-yl)-quinazolines are 1000 times more potent in in vitro PDE V enzyme than the well-known inhibitor zaprinast.

Humerus varus: a complication of neonatal, infantile, and childhood injury and infection.

Sixteen cases of humerus varus consequent to proximal humeral fracture and osteomyelitis are described. A similar, but variably severe pattern of progressive deformity occurred in all cases. The medial region of the proximal humeral physis usually either developed slowly or failed to develop, whereas the lateral region developed more normally.

Distraction osteogenesis. A comparison of corticotomy techniques.

The left hindlimbs of 15 adult mongrel dogs were lengthened using the Ilizarov external fixator. Five dogs were assigned to each of three separate groups: (I) corticotomy; (II) osteotomy with multiple drill holes and an osteotome; (III) osteotomy with an oscillating saw. Distraction began on postoperative day seven and continued at a rate of 0.

Antiarthritic profile of BF-389--a novel anti-inflammatory agent with low ulcerogenic liability.

BF-389, dihydro-4-(3,5-di-tert-butyl-4-hydroxybenzylidene)-2-methyl-2H-1,2- oxazin-3(4H)-one, is a potent, orally active, antiarthritic and analgesic agent with low ulcerogenic potential. A comparison of the activity profiles of BF-389 and naproxen showed similarities in: (1) suppression of developing and chronic adjuvant arthritis (AA); (2) maximal inhibitory response, as shown by the E(max) values in the developing and established AA models; (3) inhibition of bone degenerative changes associated with chronic adjuvant arthritis; and (4) analgesic activity in the acetic acid and phenylquinone writhing assays. Though BF-389 has been shown to be a potent inhibitor of cyclooxygenase, IC50 = 0.

Computer-automated structure evaluation (CASE) of retinoids in teratogenesis bioassays.

The potential usefulness of the retinoids, a large group of synthetic compounds chemically and structurally related to vitamin A, in the treatment of severe dermatologic diseases and in the prophylaxis and therapy against cancer is severely limited because of their potential teratogenicity. CASE analysis of published retinoid data from the hamster teratogenicity assay and the limb bud "spot" culture system has targeted the hydrophobic region of the retinoids as having the greatest effect on the range of potencies studied. In addition, log p's (as calculated by the CASE program) below a certain value appear to unilaterally result in nonteratogenic retinoids in the in vivo hamster assay system.

The structural basis of the mutagenicity of chemicals in Salmonella typhimurium: the Gene-Tox data base.

The CASE structure-activity methodology has been applied to a Gene-Tox derived Salmonella mutagenicity data base consisting of 808 chemicals. Based upon qualitative structural features, CASE identified 29 activating and 3 inactivating structural determinants which correctly predicted the probability of carcinogenicity of 93.7% of the known mutagens and non-mutagens in the data base (sensitivity = 0.

Computer-automated prediction of the mutagenicity of benzidine, 4,4"-diaminoterphenyl, 4-dimethylaminoazobenzene and 4-cyanodimethylaniline: comparison with the results of the Second UKEMS Collaborative Study.

There was agreement between the experimental results, obtained in the course of the Second UKEMS Collaborative Study, for the mutagenicity in Salmonella typhimurium of benzidine, 4,4"-diaminoterphenyl, 4-dimethylaminoazobenzene and 4-cyanodimethylaniline and the mutagenicity predicted by CASE (Computer Automated Structure Evaluation), a recently developed artificial intelligence system.

NPPD (spy dust) is predicted to be a mutagen.

With the aid of CASE, the Computer Automated Structure Evaluation system, a new artificial intelligence procedure to study structure-activity relationships and a data base consisting of 233 monocyclic nitroarenes, it is predicted that 5-(4-nitrophenyl)-2,4-pentadienal will be mutagenic for Salmonella typhimurium but that the activity will be very low.

Structure-activity relationships (SARs) among mutagens and carcinogens: a review.

This review is an introduction to methods for evaluating structure-activity relationships (SARs), and, in particular, to those methods that have been applied to study mutagenicity and carcinogenicity. A brief history and some background material on the earliest attempts to correlate molecular structure and biological activity are included. Most of the discussion focuses on modern methods utilizing extrathermodynamic and physical property variables such as the Hansch method and SIMCA, and approaches based on molecular connectivity such as the ADAPT, CASE, and Enslein methods.

Genetic and quantum chemical basis of the mutagenicity of nitroarenes for adenine-thymine base pairs.

The mutagenicity of nitroarenes for Salmonella typhimurium strains with adenine-thymine base pairs at the mutational site is dependent upon enzymic reduction of the nitro function. Although the electrophilic metabolites of nitroarenes are capable of mutating adenine-thymine base pairs, they show a marked preference for guanine-cytosine pairs when given a choice. Quantum chemical calculations indicate the reactivity order for nucleophilic sites in an AT run of base pairs to be the N-7 of adenine (N7(A)) first, followed by an approximately equal reactivity for C-8 of adenine (C8(A)) and O4 of thymine (O4(T)).

The role of DNA sequence and structure of the electrophile on the mutagenicity of nitroarenes and arylamine derivatives.

The mutagenicities of a series of nitroarenes and related electrophilic metabolites of aromatic amines were studied in Salmonella typhimurium strains TA98 and TA97, which have, respectively, (GCGC/CGCG)2 and (CCC/GGG)2 as their mutational sites. For electrophiles, primarily bicyclic species, that form adducts with nucleophilic sites other than the C8 of guanine (G), the ratios of activities in the two strains is near unity. On the other hand, for electrophiles consisting of cyclic structures with more than two rings and that are reported to react solely with the C8 of G, the ratio of activities (TA98/TA97) is in excess of 1.

Computer analysis of toxicological data bases: mutagenicity of aromatic amines in Salmonella tester strains.

There is an increasing problem in the world of toxicological evaluation in that, while test results of new compounds are appearing regularly, traditional methods of analysis of such data are cumbersome and slow. The new computer program CASE (computer automated structure evaluator) was designed to handle just such problems. It analyzes molecules and their associated biological activity on the basis of structural fragments found and identified by the program as being important for the activity based on statistical tests of significance.