Principles of early drug discovery Hughes, JP; Rees, S; Kalindjian, SB ...
British journal of pharmacology,
March 2011, Letnik:
162, Številka:
6
Journal Article
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Developing a new drug from original idea to the launch of a finished product is a complex process which can take 12–15 years and cost in excess of $1 billion. The idea for a target can come from a ...variety of sources including academic and clinical research and from the commercial sector. It may take many years to build up a body of supporting evidence before selecting a target for a costly drug discovery programme. Once a target has been chosen, the pharmaceutical industry and more recently some academic centres have streamlined a number of early processes to identify molecules which possess suitable characteristics to make acceptable drugs. This review will look at key preclinical stages of the drug discovery process, from initial target identification and validation, through assay development, high throughput screening, hit identification, lead optimization and finally the selection of a candidate molecule for clinical development.
The novel pyrrolobenzodiazocine (1) has been prepared by an intramolecular Staudinger/aza Wittig protocol from the precursor azido aldehyde (2) in a remarkable 93% yield. Aldehyde (2) was prepared by ...coupling protected homoprolinol with 2-azidobenzoic acid followed by deprotection and oxidation.
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A new molecular modeling approach has been used to derive a pharmacophore of the potent and selective cholecystokinin-2 (CCK2) receptor antagonist 5 (JB93182), based on features shared with two ...related series. The technique uses “field points” as simple and effective descriptions of the electrostatic and van der Waals maxima and minima surrounding a molecule equipped with XED (extended electron distribution) charges. Problems associated with the high levels of biliary elimination of 5 in vivo required us to design a compound with significantly lower molecular weight without sacrificing its nanomolar levels of in vitro activity. Two new series of compounds were designed to mimic the arrangement of field points present in the pharmacophore rather than its structural elements. In a formal sense, two of the three amides in 5 were replaced with either a simple pyrrole or imidazole, while some features thought to be essential for the high levels of in vitro activity of the parent compounds were retained and others deleted. These compounds maintained activity and selectivity for this receptor over CCK1. In addition, the reduction in molecular weight coupled with lower polarities greatly reduced levels of biliary elimination associated with 5. This makes them good lead compounds for development of drug candidates whose structures are not obviously related to those of the parents and represents the first example of scaffold hopping using molecular field points.
A series of 1,3,4-benzotriazepine-based CCK2 antagonists have been devised by consideration of the structural features that govern CCK receptor affinity and the receptor subtype selectivity of ...1,4-benzodiazepine-based CCK2 antagonists. In contrast to the latter compounds, these novel 1,3,4-benzotriazepines are achiral, yet they display similar affinity for CCK2 receptors to the earlier molecules and are highly selective over CCK1 receptors.
The novel
C2-fluorinated pyrrolobenzodiazepines (
1
,
2
and
3
) have been prepared from commercially available
trans-hydroxyproline in good overall yield and were screened for in vitro cytotoxicity ...against a number of cancer cell lines. The 2
R-fluoro isomer
2
exhibits an activity of 76 nM against the CH1 cell line.
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A practical and scalable operation: The reaction shown in the scheme, which uses catalytic amounts of hexacarbonyldicobalt, gives access to versatile bicyclic systems, which until now could only be ...obtained in low quantities by a photochemical process starting from tropolones. An isolation of the primary Pauson–Khand products is not necessary.
Amino alcohols have been used to introduce non‐racemic chirality into macrocycles using a modular approach that relies on a Heck macrocyclisation reaction. A wide variety of macrocycles have been ...synthesised, and their structures studied using X‐ray crystallography and molecular modelling. A fragmentation reaction encountered during the use of (S)‐1,1‐dimethylvalinol revealed that carboxylic acids generate acylals under reaction conditions often used for Heck reactions.
A modular approach that relies on a Heck macrocyclisation reaction has been used for the synthesis of macrocycles based on amino alcohols. A systematic synthetic study of a range of Heck precursors and a computational study of the Heck products have been performed. The macrocycle illustrated here is based on (S)‐prolinol and results from three head‐to‐tail Heck couplings.
The systematic optimization of the structure of a novel 2,4,5-trisubstituted imidazole-based cholecystokinin-2 (CCK2) receptor antagonist afforded analogues with nanomolar receptor affinity. These ...compounds were now comparable in their potency to the bicyclic heteroaromatic-based compounds 5 (JB93182) and 6 (JB95008), from which the initial examples were designed using a field-point based molecular modeling approach. They were also orally active as judged by their inhibition of pentagastrin stimulated acid secretion in conscious dogs, in contrast to the bicyclic heteroaromatic-based compounds, which were ineffective because of biliary elimination. Increasing the hydrophilicity through replacement of a particular methylene group with an ether oxygen, as in 3-{5-(adamantan-1-yloxymethyl)-2-cyclohexyl-1H-imidazole-4-carbonylamino}benzoic acid (53), had little effect on the receptor affinity but significantly increased the oral potency. Comparison of the plasma pharmacokinetics and the inhibition of pentagastrin-stimulated acid output following bolus intraduodenal administration of both 53 and 6 indicated that 53 was well absorbed, had a longer half-life, and was not subject to the elimination pathways of the earlier series.
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Functionalised hydroxylamine derivatives of (
S)-prolinol prepared by a Cope elimination have been found to undergo oxidation to the nitrone either in the presence of air or a catalytic ...quantity of TPAP. These undergo intramolecular cycloaddition to give tricyclic isoxazolidines with high diastereoselectivity.
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