At the forefront of new synthetic endeavors, such as drug discovery or natural product synthesis, large quantities of material are rarely available and timelines are tight. A miniaturized automation platform enabling high-throughput experimentation for synthetic route scouting to identify conditions for preparative reaction scale-up would be a transformative advance. Because automated, miniaturized chemistry is difficult to carry out in the presence of solids or volatile organic solvents, most of the synthetic "toolkit" cannot be readily miniaturized. Using palladium-catalyzed cross-coupling reactions as a test case, we developed automation-friendly reactions to run in dimethyl sulfoxide at room temperature. This advance enabled us to couple the robotics used in biotechnology with emerging mass spectrometry-based high-throughput analysis techniques. More than 1500 chemistry experiments were carried out in less than a day, using as little as 0.02 milligrams of material per reaction.

alpha(1) Adrenergic receptors mediate both vascular and lower urinary tract tone, and alpha(1) receptor antagonists such as terazosin (1b) are used to treat both hypertension and benign prostatic hyperplasia (BPH). Recently, three different subtypes of this receptor have been identified, with the alpha(1A) receptor being most prevalent in lower urinary tract tissue. This paper explores 4-aryldihydropyrimidinones attached to an aminopropyl-4-arylpiperidine via a C-5 amide as selective alpha(1A) receptor subtype antagonists. In receptor binding assays, these types of compounds generally display K(i) values for the alpha(1a) receptor subtype <1 nM while being greater than 100-fold selective versus the alpha(1b) and alpha(1d) receptor subtypes. Many of these compounds were also evaluated in vivo and found to be more potent than terazosin in both a rat model of prostate tone and a dog model of intra-urethral pressure without significantly affecting blood pressure. While many of the compounds tested displayed poor pharmacokinetics, compound 48 was found to have adequate bioavailability (>20%) and half-life (>6 h) in both rats and dogs. Due to its selectivity for the alpha(1a) over the alpha(1b) and alpha(1d) receptors as well as its favorable pharmacokinetic profile, 48 has the potential to relieve the symptoms of BPH without eliciting effects on the cardiovascular system.

This paper brings together the concepts of molecular complexity and crowdsourcing. An exercise was done at Merck where 386 chemists voted on the molecular complexity (on a scale of 1-5) of 2681 molecules taken from various sources: public, licensed, and in-house. The meanComplexity of a molecule is the average over all votes for that molecule. As long as enough votes are cast per molecule, we find meanComplexity is quite easy to model with QSAR methods using only a handful of physical descriptors (e.g., number of chiral centers, number of unique topological torsions, a Wiener index, etc.). The high level of self-consistency of the model (cross-validated R(2) ∼0.88) is remarkable given that our chemists do not agree with each other strongly about the complexity of any given molecule. Thus, the power of crowdsourcing is clearly demonstrated in this case. The meanComplexity appears to be correlated with at least one metric of synthetic complexity from the literature derived in a different way and is correlated with values of process mass intensity (PMI) from the literature and from in-house studies. Complexity can be used to differentiate between in-house programs and to follow a program over time.

In an effort to discover potent, clinically useful thrombin inhibitors, a rapid analogue synthetic approach was used to explore the P(1) region. Various benzylamines were coupled to a pyridine/pyrazinone P(2)-P(3) template. One compound with an o-thiadiazole benzylic substitution was found to have a thrombin K(i) of 0.84 nM. A study of ortho-substituted five-membered-ring heterocycles was undertaken and subsequently demonstrated that the o-triazole and tetrazole rings were optimal. Combination of these potent P(1) aryl heterocycles with a variety of P(2)-P(3) groups produced a compound with an extraordinary thrombin inhibitory activity of 1.4 pM. It is hoped that this potency enhancement in P(1) will allow for more diversification in the P(2)-P(3) region to ultimately address additional pharmacological concerns.

␤-Site amyloid precursor protein (APP)-cleaving enzyme (BACE) 1 cleavage of amyloid precursor protein is an essential step in the generation of the potentially neurotoxic and amyloidogenic A␤42 peptides in Alzheimer's disease. Although previous mouse studies have shown brain A␤ lowering after BACE1 inhibition, extension of such studies to nonhuman primates or man was precluded by poor potency, brain penetration, and pharmacokinetics of available inhibitors. In this study, a novel tertiary carbinamine BACE1 inhibitor, tertiary carbinamine (TC)-1, was assessed in a unique cisterna magna ported rhesus monkey model, where the temporal dynamics of A␤ in cerebrospinal fluid (CSF) and plasma could be evaluated. TC-1, a potent inhibitor (IC 50 ϳ 0.4 nM), has excellent passive membrane permeability, low susceptibility to P-glycoprotein transport, and lowered brain A␤ levels in a mouse model. Intravenous infusion of TC-1 led to a significant but transient lowering of CSF and plasma A␤ levels in conscious rhesus monkeys because it underwent CYP3A4-mediated metabolism. Oral codosing of TC-1 with ritonavir, a potent CYP3A4 inhibitor, twice daily over 3.5 days in rhesus monkeys led to sustained plasma TC-1 exposure and a significant and sustained reduction in CSF sAPP␤, A␤40, A␤42, and plasma A␤40 levels. CSF A␤42 lowering showed an EC 50 of ϳ20 nM with respect to the CSF [TC-1] levels, demonstrating excellent concordance with its potency in a cell-based assay. These results demonstrate the first in vivo proof of concept of CSF A␤ lowering after oral administration of a BACE1 inhibitor in a nonhuman primate.

The total synthesis of the potent PAF antagonist ginkgolide B has been accomplished. The complex architecture of ginkgolide B which includes six rings, eleven stereogenic centers, ten oxygenated carbons, and four contiguous fully substituted carbons is a daunting challenge for chemical synthesis. The synthesis of ginkgolide B was accomplished through a stereoselective intramolecular photocycloaddition of enone 5 to construct the congested core of the molecule. The photocycloaddition substrate was prepared through technology for the construction of carboalkoxycyclopentenones previously reported from these laboratories. Regioselective cyclobutane fragmentation and further functionalization of the photoadduct 4 provided the key pentacyclic intermediate. Acid-catalyzed rearrangement and epoxide opening were key transformations in the production of ginkgolide B from the pentacyclic intermediate.Ginkgo biloba, one of the oldest surviving flora with ancestors dating to 230 million B.C., flourished during the Jurassic Period and has been called the "living fossil" by Charles Darwin. 1 The ginkgo tree survives today because of its extraordinary resilience, having endured several planetary mass extinctions of plant life. Its regenerative powers are supported by a report that a ginkgo tree sprouted anew from its roots at ground zero Hiroshima. Extracts of G. biloba have been used as herbal medicines for approximately 5000 years to treat a variety of ailments including coughs, asthma, and circulatory disorders. The traditional Hindu medicine "soma" also contains ginkgo extracts, and recent clinical studies attest to possible benefits of ginkgolides in the delay in the onset of dementia. 2 Ginkgolides A, B, C, and M (Figure 1), which differ only in the number and location of hydroxyl groups, were first isolated as "bitter principles" of the root bark by Furukawa and co-workers in 1932. 3 The structures of the ginkgolides were first elucidated in 1967 by a series of spectroscopic studies by Nakanishi. 4 The assigned structures were independently confirmed by X-ray crystallography by the Okabe group at Nagoya University. 5 A related C15 compound, bilobalide, was discovered in 1971, 6,7 and in 1987, another member of the ginkgolide family, ginkgolide J, was isolated and characterized. 8 Ginkgolide B is the most potent platelet-activating factor (PAF) antagonist of the ginkgo extracts with an IC 50 value of 0.6 mM. 9 Because of its portentous molecular architecture, ginkgolide B is an intimidating challenge for chemical synthesis. Included in the ginkgolide skeleton are six rings, eleven stereogenic centers, ten oxygenated carbons, an unusual tert-butyl group, 10 and four contiguous fully substituted carbon atoms. At the sterically congested core of the molecule are quaternary carbons C5 and C9, which are jointly embodied in five of the six rings of the molecule. The stereogenically correct installation of the C5 and C9 quaternary carbons and the proper orchestration of functional group manipulation are the most critical iss...

We describe the discovery and optimization of tertiary carbinamine derived inhibitors of the enzyme beta-secretase (BACE-1). These novel non-transition-state-derived ligands incorporate a single primary amine to interact with the catalytic aspartates of the target enzyme. Optimization of this series provided inhibitors with intrinsic and functional potency comparable to evolved transition state isostere derived inhibitors of BACE-1.

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