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BACKGROUND Over the past century, innovations in synthetic chemistry have greatly enabled the discovery and development of important life-changing medicines, improving the health of patients worldwide. In recent years, many pharmaceutical companies have chosen to reduce their R&D investment in chemistry, viewing synthetic chemistry more as a mature technology and less as a driver of innovation in drug discovery. Contrary to this opinion, we believe that excellence and innovation in synthetic chemistry continue to be critical to success in all phases of drug discovery and development. Moreover, recent developments in new synthetic methods, biocatalysis, chemoinformatics, and reaction miniaturization have the power to accelerate the pace and improve the quality of products in pharmaceutical research. Indeed, the application of new synthetic methods is rapidly expanding the realm of accessible chemical matter for modulating a broader array of biological targets, and there is a growing recognition that innovations in synthetic chemistry are changing the practice of drug discovery. We identify some of the most enabling recent advances in synthetic chemistry as well as opportunities that we believe are poised to transform the practice of drug discovery and development in the coming years. ADVANCES Over the past century, innovations in synthetic methods have changed the way scientists think about designing and building molecules, enabling access to more expansive chemical space and to molecules possessing the essential biological activity needed in future investigational drugs. In order for the pharmaceutical industry to continue to produce breakthrough therapies that address global health needs, there remains a critical need for invention of synthetic transformations that can continue to drive new drug discovery. Toward this end, investment in research directed toward synthetic methods innovation, furthering the nexus of synthetic chemistry and biomolecules, and developing new technologies to accelerate methods discovery is essential. One powerful example of an emerging, transformative synthetic method is the recent discovery of photoredox catalysis, which allows one to harness the energy of visible light to accomplish synthetic transformations on drug-like molecules that were previously unachievable. Furthermore, recent breakthroughs in molecular biology, bioinformatics, and protein engineering are driving rapid identification of biocatalysts that possess desirable stability, unique activity, and exquisite selectivity needed to accelerate drug discovery. Recent developments in the merging fields of synthetic and biosynthetic chemistry have sought to harness these molecules in three distinct ways: as biocatalysts for novel and selective transformations, as conjugates through innovative bio-orthogonal chemistry, and in the development of improved therapeutic modalities. The development of high-throughput experimentation and analytical tools for chemistry has made it possible to execute more than 1500 simultaneous experiments at microgram scale in 1 day, enabling the rapid identification of suitable reaction conditions to explore chemical space and accelerate drug discovery. Finally, advances in computational chemistry and machine learning in the past decade are delivering real impact in areas such as new catalyst design, reaction prediction, and even new reaction discovery. OUTLOOK These advances position synthetic chemistry to continue to have an impact on the discovery and development of the next generation of medicines. Key unsolved problems in synthetic chemistry with potential implications for drug discovery include selective saturation and functionalization of heteroaromatics; concise synthesis of highly functionalized, constrained bicyclic amines; and C-H functionalization for the synthesis of α,α,α-trisubstituted amines. Other areas, such as site-selective modification of biomolecules and synthesis of noncanonical nucleosides, are emerging as opportunities of high potential impact. The concept of molecular editing, whereby one could selectively insert, delete, or exchange atoms in highly elaborated molecules, is an area of emerging interest. Continued investment in synthetic chemistry and chemical technologies through partnerships between the pharmaceutical industry and leading academic groups holds great promise to advance the field closer to a state where exploration of chemical space is unconstrained by synthetic complexity and only limited by the imagination of the chemist, enabling the discovery of the optimal chemical matter to treat disease faster than ever before.

Affinity selection screening of macrocycle libraries derived from DNA-programmed chemistry identified XIAP BIR2 and BIR3 domain inhibitors that displace bound pro-apoptotic caspases. X-ray cocrystal structures of key compounds with XIAP BIR2 suggested potency-enhancing structural modifications. Optimization of dimeric macrocycles with similar affinity for both domains were potent pro-apoptotic agents in cancer cell lines and efficacious in shrinking tumors in a mouse xenograft model.

Introduction TPN729MA is a newly developed phosphodiesterase type 5 inhibitor (PDE5i) for the treatment of erectile dysfunction, which offers potential for greater selectivity and longer duration of action than PDE5i in current clinical use. Aim We investigated the in vitro inhibitory potency and selectivity of TPN729MA on PDE isozymes, and its efficacy in animal models. Methods The inhibition of 11 human recombinant PDEs by TPN729MA, sildenafil, and tadalafil were determined using radioimmunoassay. The effect of TPN729MA and sildenafil on intracavernous pressure (ICP), blood pressure (BP), and ICP/BP ratio were determined in a rat model of erection induced by electric stimulation and in a dog model of erection induced by sodium nitroprusside injection. Main Outcome Measures The main outcome measures were IC 50 of TPN729MA, sildenafil, and tadalafil for PDE1-PDE11; maximum ICP; BP and ICP/BP ratio. Results The IC 50 of TPN729MA, sildenafil, and tadalafil for PDE5 was 2.28, 5.22, and 2.35 nM, respectively. TPN729MA showed 248, 366, 20, and 2671-fold selectivity against PDE1, PDE4, PDE6, and PDE11, respectively. TPN729MA showed excellent selectivity against PDE2, 3, 7, 8, 9, and 10 (>10,000-fold). In the rat model of erection, TPN729MA (5.0 and 2.5 mg/kg), but not sildenafil, significantly increased the maximum ICP compared with vehicle. Significantly increased ICP/BP was observed in the TPN729MA (5.0 mg/kg) group at all time points, in the TPN729MA (2.5 mg/kg) group at 75, 90, 105, and 120 minutes time points, and in sildenafil group at 75 and 90 minutes time points compared with vehicle. In the dog model of erection, TPN729MA and sildenafil significantly increased ICP and ICP/BP but showed no significant effect on BP compared with vehicle. Conclusions TPN729MA is a potent PDE5i with a balanced selectivity profile. TPN729MA shows excellent in vitro and in vivo potency, and a longer effect on erectile function than sildenafil in animal model. Wang Z, Zhu D, Yang X, Li J, Jiang X, Tian G, Terrett NK, Jin J, Wu H, He Q, Yang B, and Shen J. The selectivity and potency of the new PDE5 Inhibitor TPN729MA. J Sex Med 2013;10:2790–2797.

36 new compounds with the typical skeleton of 4-anilino-5-vinyl/ethynyl pyrimidine, 4-anilino-3-cyano-5-vinyl/ethynyl/phenyl pyridine, and m-amino-N-phenylbenzamide, are designed, synthesized and selectively tested on EGFR, ErbB-2 kinases, and A-549, HL60 cells growth inhibition. Results from the bioactivity and chemical structures yield preliminary structure-activity relationships (SARs). The most potent 5-ethynylpyrimidine derivative 20a has an IC50 value of 45 nM to EGFR kinase. Several compounds of other series also show IC50 values

Cyclic nucleotide phosphodiesterase type 5 (PDE5) is a prime drug target for treating the diseases associated with a lower level of the cyclic guanosine monophosphate (cGMP), which is a specific substrate for PDE5 hydrolysis. Here we report a series of novel PDE5 inhibitors with the new scaffold of the monocyclic pyrimidin-4(3H)-one ring developed using the structure-based discovery strategy. In total, 37 derivatives of the pyrimidin-4(3H)-ones, were designed, synthesized, and evaluated for their inhibitory activities to PDE5, resulting in 25 compounds with IC50 ranging from 1 to 100 nM and 11 compounds with IC50 ranging from 1 to 10 nM. Compound 5, 5,6-diethyl-2-[2-n-propoxy-5-(4-methyl-1-piperazinylsulfonyl)phenyl]pyrimid-4(3H)-one, the most potent compound, has an excellent IC50 (1.6 nM) in vitro and a good efficacy in a rat model of erection. It thus provides a potential candidate for the further development into a new drug targeting PDE5.

Macrocycles are found widely in nature where they fulfill numerous specific functions. However they have been generally underexploited as drug molecules, as they are larger than more conventional ‘Rule of 5’ compliant molecules and their synthesis and screening has been considered a challenge. Consequently most pharmaceutical companies have very few macrocycles in their screening files, and yet these compounds can have potent and selective pharmacological activity, and exhibit drug-like properties such as cell membrane permeability and oral bioavailability. To permit the further investigation of macrocyclic drugs, several groups have developed diverse methods for the rapid synthesis and screening of macrocyclic libraries.

A series of dimeric macrocyclic compounds were prepared and evaluated as antagonists for inhibitor of apoptosis proteins. The most potent analogue 11, which binds to XIAP and c-IAP proteins with high affinity and induces caspase-3 activation and ultimately cell apoptosis, inhibits growth of human melanoma and colorectal cell lines at low nanomolar concentrations. Furthermore, compound 11 demonstrated significant antitumor activity in the A875 human melanoma xenograft model at doses as low as 2 mg/kg on a q3d schedule.

A propargylic alcohol 24 with the propynyl group exo on the norbornene framework was used in a stereospecific synthesis of the mixture of allylsilanes 27 and 28. The stereospecific reaction of this mixture with peracid gave, with a high level of stereocontrol, the norbornenol 25 having the alkenyl group endo on the norbornene framework. This substrate underwent an oxyanion accelerated Cope rearrangement setting up all four stereocentres in a synthesis of (±)-dihydronepetalactone 6.

Through the advantages conferred in the speed of synthesis, combinatorial chemistry is making a significant impact on the process of drug discovery. The mix-and-split paradigm has been an effective method for the production of compound mixtures, although there is now a need for new, fast library approaches to generate well-characterised single compounds. Having already demonstrated the successful preparation and application of library mixtures, we have now developed a novel combinatorial method for the production of single compounds.

5-(2′-Alkoxyphenyl)pyrazolo[4,3-d]pyrimidin-7-ones, and in particular our preferred compound, sildenafil (VIAGRATM), discovered through a rational drug design programme, are potent and selective inhibitors of the type 5 cGMP phosphodiesterase from both rabbit platelets and human corpus cavernosum. Sildenafil is currently in the clinic for the oral treatment of male erectile dysfunction.

Parallel compound synthesis enables large numbers of individual compounds to be prepared simultaneously using semiautomated techniques. This fast and efficient methodology has an important role to play in accelerating lead optimisation and hence the whole drug discovery process. The potential of this strategy to rapidly optimise chemical leads and provide structure-activity relationship (SAR) information was demonstrated in two therapeutic areas, antiviral agents (herpes simplex virus), and neurokinin-2 receptor antagonists.

Radical cyclisation of sp 3 carbon-centred radicals onto imines and hydrazones provides a new method for the synthesis of 5- and 6-membered ring nitrogen heterocycles. Cyclisation onto the electrophilic carbon of the C=N group and 5- exo stereoelectronic selectivity are the dominating mechanistic parameters. The C-centred radical intermediates were generated from benzeneselenyl precursors using Bu 3 SnH.

A combinatorial library of 30,752 compounds has been synthesised from a set of 32 natural and unnatural amino acids. The library was designed to include the known endothelin antagonist, FR-139,317, as a positive control, and this and a number of close analogues were shown to be the most potent compounds. Thus, combinatorial libraries may be used both to discover leads and rapidly explore SAR. A combinatorial library of 30,752 compounds has been synthesised from a set of 32 natural and unnatural amino acids. The library was designed to include the known endothelin antagonist, FR-139,317, as a positive control, and this and a number of close analogues were shown to be the most potent compounds. Thus, combinatorial libraries may be used both to discover leads and rapidly explore SAR.

The regioselectivity of intramolecular addition of sp3 carbon-centred radicals onto CN double bonds of imines and hydrazones is influenced by the position and polarisation of the CN bond.

Reaction of a number of 1,6-diene or enyne systems with TolSO 2 SePh, under free radical conditions, results in selenosulfonylation with concomitant CC bond formation, to give cyclised alkyl or vinyl sulfones containing the synthetically useful phenylselenyl functionality. Similar cyclisations are possible by using Ph 2 PH in place of TolSO 2 SePh, resulting in the formation of cyclic phosphine or vinyl phosphine products, although in these reactions the diene substrates give rather modest yields.

Reaction of diphenylphosphine with suitable 1,6-diene or enyne systems, under free radical conditions, results in addition of a phosphorus-centred radical and cyclisation to form substituted phosphines and vinyl phosphines respectively.

Reaction of a number of 1,6-diene or enyne systems with TolSO 2 SePh, under free radical condition, results in selenosulphonylation with concommitant CC bond formation, to give cyclised alkyl or vinyl sulphones containing the synthetically useful phenylselenyl functionality.

Simmons-Smith type methylenation of allylsilanes, followed by protodesilylation, can be used to achieve overall the S E 2' replacement of the silyl group by a methyl group. The regioselectivity is good for protonation on the methylene carbon of the cyclopropylmethylsilanes 11, 17, 20 and 23, but the low stereoselectivity in the formation of the cyclopropylmethylsilane 26 and its failure to undergo clean protodesilylation make the method of limited use

5-(2′-Alkoxyphenyl)pyrazolo[4,3-d]pyrimidin-7-ones, and in particular our preferred compound, sildenafil (VIAGRATM), discovered through a rational drug design programme, are potent and selective inhibitors of the type 5 cGMP phosphodiesterase from both rabbit platelets and human corpus cavernosum. Sildenafil is currently in the clinic for the oral treatment of male erectile dysfunction.

Through the advantages conferred in the speed of synthesis, combinatorial chemistry is making a significant impact on the process of drug discovery. The mix-and-split paradigm has been an effective method for the production of compound mixtures, although there is now a need for new, fast library approaches to generate well-characterised single compounds. Having already demonstrated the successful preparation and application of library mixtures, we have now developed a novel combinatorial method for the production of single compounds.

A propargylic alcohol 24 with the propynyl group exo on the norbornene framework was used in a stereospecific synthesis of the mixture of allylsilanes 27 and 28. The stereospecific reaction of this mixture with peracid gave, with a high level of stereocontrol, the norbornenol 25 having the alkenyl group endo on the norbornene framework. This substrate underwent an oxyanion accelerated Cope rearrangement setting up all four stereocentres in a synthesis of (±)-dihydronepetalactone 6.

Simmons-Smith type methylenation of allylsilanes, followed by protodesilylation, can be used to achieve overall the S E 2' replacement of the silyl group by a methyl group. The regioselectivity is good for protonation on the methylene carbon of the cyclopropylmethylsilanes 11, 17, 20 and 23, but the low stereoselectivity in the formation of the cyclopropylmethylsilane 26 and its failure to undergo clean protodesilylation make the method of limited use

Macrocyclic natural products have evolved to fulfil numerous biochemical functions, and their profound pharmacological properties have led to their development as drugs. A macrocycle provides diverse functionality and stereochemical complexity in a conformationally pre-organized ring structure. This can result in high affinity and selectivity for protein targets, while preserving sufficient bioavailability to reach intracellular locations. Despite these valuable characteristics, and the proven success of more than 100 marketed macrocycle drugs derived from natural products, this structural class has been poorly explored within drug discovery. This is in part due to concerns about synthetic intractability and non-drug-like properties. This Review describes the growing body of data in favour of macrocyclic therapeutics, and demonstrates that this class of compounds can be both fully drug-like in its properties and readily prepared owing to recent advances in synthetic medicinal chemistry.

A variety of spiroether products, including one bis-spiro compound, are available via a simple radical cyclisation route.

A library, evaluating a range of piperazines, piperidines and acyclic amines, as replacements for the 4-hydroxy-4-phenylpiperidine moiety in lead (1b) was prepared. These efforts identified the 4-((N)-benzimidazolone)piperidine analogue (2a) which was further optimised using classical single-compound synthesis to yield the 3-((N)-morpholino)azetidine (2j). Conformationally constrained analogues of (2j), generally offered no potency advantage in this particular series.

A search for potent inhibitors of EC 3.4.24.11, an enzyme which is found most abundantly in the kidney and which degrades atrial natriuretic factor, has led to the identification of UK-69,578. Structure-activity studies starting from substituted N-carboxymethyl dipeptide inhibitors resulted in the introduction of a cyclo-alkane P1' residue and in the replacement of the aza-link between P1 and P1' residues by a methylene group, with a net ten-fold potency gain. UK-69,578 increases endogenous ANF levels and produces natriuretic and diuretic responses intravenously in mice.

The SE2′ reactions of 1 and 2 with a range of electrophiles are predominantly anti in the allylsilane portion of the molecule, but this is offset, to a greater or lesser extent, by axial or equatorial preferences in the ring system.

The stereospecifically anti synthesis of allyl- and allenyl-silanes by the reaction of a silylcuprate reagent with allyl and propargyl acetates is described. The S E 2′ reactions of these silanes with various electrophiles are shown to proceed with predominantly anti stereoselectivity, offset to a greater or lesser extent by other steric factors.

The use of radical cyclisations allows direct access to a family of azaspirocyclic ketones, including compounds having the azaspiro[4.4]nonane, and azaspiro[5.5]undecane structures which are found in the alkaloids cephalotaxine and histrionicotoxin.

Alcohols bearing suitable chains for radical initiation are smoothly condensed with cyclic β-diketones to afford systems which undergo radical cyclisation to give various spiroether products.

The tertiary allylic acetates (1–4) and the propargylic acetates (14 and 15) react with our silyl-cuprate reagent (5) to give, in a cleanly anti manner, the stereodefined allylsilanes (6 and 7) and allenylsilanes (16 and 17).

A stereospecific synthesis of allylsilanes and their stereospecific reaction with peracid are used to prepare the endo-prop-1-enylnorbornenol (6), a substrate for an oxy-Cope rearrangement leading eventually to dihydronepetalactone (10) with complete stereocontrol.