Despite decades of ground-breaking research in academia, organic synthesis is still a rate-limiting factor in drug-discovery projects. Here we present some current challenges in synthetic organic ...chemistry from the perspective of the pharmaceutical industry and highlight problematic steps that, if overcome, would find extensive application in the discovery of transformational medicines. Significant synthesis challenges arise from the fact that drug molecules typically contain amines and N-heterocycles, as well as unprotected polar groups. There is also a need for new reactions that enable non-traditional disconnections, more C-H bond activation and late-stage functionalization, as well as stereoselectively substituted aliphatic heterocyclic ring synthesis, C-X or C-C bond formation. We also emphasize that syntheses compatible with biomacromolecules will find increasing use, while new technologies such as machine-assisted approaches and artificial intelligence for synthesis planning have the potential to dramatically accelerate the drug-discovery process. We believe that increasing collaboration between academic and industrial chemists is crucial to address the challenges outlined here.
Sickle-cell disease Rees, David C, Dr; Williams, Thomas N, PhD; Gladwin, Mark T, Prof
The Lancet (British edition),
12/2010, Letnik:
376, Številka:
9757
Journal Article
Recenzirano
Summary Sickle-cell disease is one of the most common severe monogenic disorders in the world. Haemoglobin polymerisation, leading to erythrocyte rigidity and vaso-occlusion, is central to the ...pathophysiology of this disease, although the importance of chronic anaemia, haemolysis, and vasculopathy has been established. Clinical management is basic and few treatments have a robust evidence base. One of the main problems of sickle-cell disease in children is the development of cerebrovascular disease and cognitive impairment, and the role of blood transfusion and hydroxycarbamide for prevention of these complications is starting to be understood. Recurrent episodes of vaso-occlusion and inflammation result in progressive damage to most organs, including the brain, kidneys, lungs, bones, and cardiovascular system, which becomes apparent with increasing age. Most people with sickle-cell disease live in Africa, where little is known about this disease; however, we do know that the disorder follows a more severe clinical course in Africa than for the rest of the world and that infectious diseases have a role in causing this increased severity of sickle-cell disease. More work is needed to develop effective treatments that specifically target pathophysiological changes and clinical complications of sickle-cell disease.
Update review of the acute porphyrias Stein, Penelope E.; Badminton, Michael N.; Rees, David C.
British journal of haematology,
February 2017, Letnik:
176, Številka:
4
Journal Article
Recenzirano
Odprti dostop
Summary
Acute porphyrias are rare inherited disorders due to deficiencies of haem synthesis enzymes. To date, all UK cases have been one of the three autosomal dominant forms, although penetrance is ...low and most gene carriers remain asymptomatic. Clinical presentation is typically with acute neurovisceral attacks characterised by severe abdominal pain, vomiting, tachycardia and hypertension. Severe attacks may be complicated by hyponatraemia, peripheral neuropathy sometimes causing paralysis, seizures and psychiatric features. Attacks are triggered by prescribed drugs, alcohol, hormonal changes, fasting or stress. The diagnosis is made by finding increased porphobilinogen excretion in a light‐protected random urine sample. Management includes administration of intravenous human haemin and supportive treatment with non‐porphyrinogenic drugs. A few patients develop recurrent attacks, a chronic illness requiring specialist management. Late complications include chronic pain, hepatocellular carcinoma, chronic renal failure and hypertension. In the UK, the National Acute Porphyria Service provides clinical advice and supplies haemin when indicated.
Sickle Cell Disease Piel, Frédéric B; Steinberg, Martin H; Rees, David C
The New England journal of medicine,
04/2017, Letnik:
376, Številka:
16
Journal Article
Recenzirano
Odprti dostop
Sickle cell disease is caused by an alteration in a single DNA base, but its clinical manifestations are influenced by other genes and behavioral and environmental factors. Recent findings may ...indicate an acceleration in the discovery of interventions that alter the disease course.
Sickle cell disease is an increasing global health problem. Estimates suggest that every year approximately 300,000 infants are born with sickle cell anemia, which is defined as homozygosity for the sickle hemoglobin (HbS) gene (i.e., for a missense mutation Glu6Val, rs334 in the β-globin gene
HBB
) and that this number could rise to 400,000 by 2050.
1
Although early diagnosis, penicillin prophylaxis, blood transfusion, transcranial Doppler imaging, hydroxyurea, and hematopoietic stem-cell transplantation can dramatically improve survival and quality of life for patients with sickle cell disease, our understanding of the role of genetic and nongenetic factors in explaining the . . .
In a randomized phase 3 trial involving patients with acute intermittent porphyria, the use of givosiran, an oligonucleotide drug designed to target messenger RNA encoding aminolevulinic acid ...synthase, led to a 74% lower annualized porphyria attack rate than the use of placebo at 6 months.
The search for new drugs is plagued by high attrition rates at all stages in research and development. Chemists have an opportunity to tackle this problem because attrition can be traced back, in ...part, to the quality of the chemical leads. Fragment-based drug discovery (FBDD) is a new approach, increasingly used in the pharmaceutical industry, for reducing attrition and providing leads for previously intractable biological targets. FBDD identifies low-molecular-weight ligands (∼150 Da) that bind to biologically important macromolecules. The three-dimensional experimental binding mode of these fragments is determined using X-ray crystallography or NMR spectroscopy, and is used to facilitate their optimization into potent molecules with drug-like properties. Compared with high-throughput-screening, the fragment approach requires fewer compounds to be screened, and, despite the lower initial potency of the screening hits, offers more efficient and fruitful optimization campaigns. Here, we review the rise of FBDD, including its application to discovering clinical candidates against targets for which other chemistry approaches have struggled.
What’s a good fragment? Fragment‐based drug discovery is well‐established within many pharmaceutical, biotech, and academic institutions for generating new drugs. In this Essay, the opportunities and ...challenges for organic chemists to design and synthesize new fragments are described.
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