Preclinical strategies that are used to identify potential drug candidates include target-based screening, phenotypic screening, modification of natural substances and biologic-based approaches. To investigate whether some strategies have been more successful than others in the discovery of new drugs, we analysed the discovery strategies and the molecular mechanism of action (MMOA) for new molecular entities and new biologics that were approved by the US Food and Drug Administration between 1999 and 2008. Out of the 259 agents that were approved, 75 were first-in-class drugs with new MMOAs, and out of these, 50 (67%) were small molecules and 25 (33%) were biologics. The results also show that the contribution of phenotypic screening to the discovery of first-in-class small-molecule drugs exceeded that of target-based approaches — with 28 and 17 of these drugs coming from the two approaches, respectively — in an era in which the major focus was on target-based approaches. We postulate that a target-centric approach for first-in-class drugs, without consideration of an optimal MMOA, may contribute to the current high attrition rates and low productivity in pharmaceutical research and development.

How were new medicines discovered

Memantine is a clinically well tolerated N-methyl-d-aspartate (NMDA) receptor antagonist—a review of preclinical data

Memantine: a NMDA receptor antagonist that improves memory by restoration of homeostasis in the glutamatergic system--too little activation is bad, too much is even worse.

/pdf/the-lipophilic-bullet-hits-the-targets-medicinal-chemistry-5f1wikoz3q.pdf

The Lipophilic Bullet Hits the Targets: Medicinal Chemistry of Adamantane Derivatives

We have used a structure-activity approach to investigate whether the Vinca alkaloids inhibit cell proliferation primarily by means of their effects on mitotic spindle microtubules or by another mechanism or by a combination of mechanisms. Five Vinca alkaloids were used to investigate the relationship in HeLa cells between inhibition of cell proliferation and blockage of mitosis, alteration of spindle organization, and depolymerization of microtubules. Indirect immunofluorescence staining of microtubules and 4,6-diamidino-2-phenylindole staining of chromatin were used to characterize the effects of the drugs on the distributions of cells in stages of the cell cycle and on the organization of microtubules and chromosomes in metaphase spindles. The microtubule polymer was isolated from cells and quantified using a competitive enzyme-linked immunoadsorbent assay for tubulin. We observed a nearly perfect coincidence between the concentration of each Vinca derivative that inhibited cell proliferation and the concentration that caused 50% accumulation of cells at metaphase, despite the fact that the antiproliferative potencies of the drugs varied over a broad concentration range. Inhibition of cell proliferation and blockage of cells at metaphase at the lowest effective concentrations of all Vinca derivatives occurred with little or no microtubule depolymerization or spindle disorganization. With increasing drug concentrations, the organization of microtubules and chromosomes in arrested mitotic spindles deteriorated in a manner that was common to all five congeners. These results indicate that the antiproliferative activity of the Vinca alkaloids at their lowest effective concentrations in HeLa cells is due to inhibition of mitotic spindle function. The results suggest further that the Vinca alkaloids inhibit cell proliferation by altering the dynamics of tubulin addition and loss at the ends of mitotic spindle microtubules rather than by depolymerizing the microtubules. The specific alterations of spindle microtubule dynamics appear to differ among the five Vinca congeners, and such differences may be responsible for differences in the antitumor specificities of the drugs.

https://cancerres.aacrjournals.org/content/canres/51/8/2212.full.pdf

Mechanism of Inhibition of Cell Proliferation by Vinca Alkaloids

Exploration of the effects of "minor" structural differences on the antitumor activity and toxicity of dimeric Catharanthus alkaloids resulted in the preparation of deacetylvinblastine amide (vindesine, VDS) from either vinblastine (VLB) or deacetylvinblastine. Adequate amounts of vindesine for biological testing were prepared by preferential hydrazinolysis of the C23-ester in the vindoline moiety of VLB, followed by hydrogenolysis of the resulting deacetylvinblastine hydrazide. Vindesine in its activity spectrum against rodent tumor systems resembles vincristine (VCR) rather than its parent VLB, while its neurotoxic potential appears to be less than that of VCR. The experimental models developed to estimate this potential include in vitro measurements of axoplasmic transport effects in the cat sciatic nerve and the estimation of neuromuscular disturbances in chickens and monkeys by vindesine in comparison with VCR. A radioimmunoassay for VLB, VCR, and VDS, developed by means of deacetylvinblastine acid azide, has been used to study the pharmacokinetics of vindesine in man. The clinical investigation of vindesine is in progress. Deacetylvinblastine, in contrast to earlier reports, showed activity against several murine tumor systems.

Structure-activity relationships of dimeric Catharanthus alkaloids. 1. Deacetylvinblastine amide (vindesine) sulfate.

The adamantyl group in medicinal agents. i. hypoglycemic n-arylsulfonyl-n' -adamantylureas.

The adamantyl group in medicinal agents. 3. Nucleoside 5'-adamantoates. The adamantoyl function as a protecting group.

While structure-activity relationships for vinblastine (VLB), vincristine, deacetyl-VLB, and deacetyl-VLB amide (vindesine, VDS) in several tumor and leukemia models have been reported previously, the present study explores these relationships for a series of N-substituted vindesine analogues. These compounds were prepared from the reaction of deacetyl-VLB acid azide with the appropriate amines and were characterized by mass spectral analysis, 1H and 13C NMR spectra, electrometric titration, and infrared spectra. N-Alkylvindesines have reduced activity compared to that of VDS against the Gardner lymphosarcoma (GLS). N-beta-Hydroxyethyl-VDS surpasses vindesine in its activity against the Ridgway osteogenic sarcoma and the GLS, whereas against the B16 melanoma it is less active than VDS. N-beta-(4-Hydroxyphenethyl)-VDS, envisaged as a substrate for the enzyme tryosinase, was shown to be more active than VDS against the B16 melanoma but has only marginal activity against the GLS. In terms of collective antitumor activity against the model systems used, vindesine emerges as the congener with optimum qualities. Bis(N-ethylidenevindesine) disulfide, the first example of a bridged bisvindesine and comparable to VDS in its antitumor profile, shows evidence of activity against a P388/VCR leukemia strain known to be resistant to maytansine as well as to vincristine.

Structure-activity relationships of dimeric Catharanthus alkaloids. 2. Experimental antitumor activities of N-substituted deacetylvinblastine amide (vindesine) sulfates.

Electrophysiological effects of ryanodine derivatives on the sheep cardiac sarcoplasmic reticulum calcium-release channel

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