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Polymorphism occurs widely in pharmaceutical solids, and must be thoroughly studied during product development. Twenty-four years after ritonavir (RTV) Form II materialized, we report a new polymorph, Form III, discovered via melt crystallization. Form III has a unique PXRD pattern, Raman spectrum, lower melting point and heat of fusion, compared to the known polymorphs, Form I and Form II. It is the least stable form, monotropically, among the three polymorphs. Form III differs from Form I and Form II in molecular conformation and hydrogen bonding motifs in crystal lattice. Nucleation from RTV supercooled liquid is slow, and selected Form III exclusively. The discovery of RTV Form III demonstrates the importance of crystal nucleation studies. Crystallization from supercooled liquids should be incorporated as part of polymorph screening workflow.

A thymol:4,4'-dipyridyl (2:1) cocrystal (Form I) is reported to suppress thymol sublimation. The cocrystal was prepared via solution-mediated phase transformation and its structure is sustained by O-H (phenol) ··· N (pyridyl) hydrogen bonds between two individual components. A cocrystal polymorph (Form II) was formed via solid state transformation or via vapor phase upon heating. Using gravimetry analysis, it was demonstrated that cocrystal Form I decreased the sublimation rate of thymol by 38-fold. This study demonstrates that cocrystallization is an effective approach to reduce vapor pressure and sublimation of solids, thus achieving odor-masking.

Using a convergent synthetic route to enable multiple points of diversity, a series of glucocorticoid receptor modulators (GRM) were profiled for potency, selectivity, and drug-like properties

Dasabuvir is a non-nucleoside polymerase inhibitor for the treatment of hepatitis C virus (HCV) infection. It is an extremely weak diacidic drug (p

Direct-acting antiviral regimens have transformed therapeutic management of hepatitis C across all prevalent genotypes. Most of the chemical matter in these regimens comprises molecules well outside the traditional drug development chemical space and presents significant challenges. Herein, the implications of high conformational flexibility and the presence of a 15-membered macrocyclic ring in paritaprevir are studied through a combination of advanced computational and experimental methods with focus on molecular chameleonicity and crystal form complexity. The ability of the molecule to toggle between high and low 3D polar surface area (PSA) conformations is underpinned by intramolecular hydrogen bonding (IMHB) interactions and intramolecular steric effects. Computational studies consequently show a very significant difference of over 75 A2 in 3D PSA between polar and apolar environments and provide the structural basis for the perplexingly favorable passive permeability of the molecule. Crystal packing and protein binding resulting in strong intermolecular interactions disrupt these intramolecular interactions. Crystalline Form I benefits from strong intermolecular interactions, whereas the weaker intermolecular interactions in Form II are partially compensated by the energetic advantage of an IMHB. Like Form I, no IMHB is observed within the receptor-bound conformation; instead, an intermolecular H-bond contributes to the potency of the molecule. The choice of metastable Form II is derisked through strategies accounting for crystal surface and packing features to manage higher form specific solid-state chemical reactivity and specific processing requirements. Overall, the results show an unambiguous link between structural features and derived properties from crystallization to dissolution, permeation, and docking into the protein pocket.

The high cost and negative environmental impact of precious metal catalysts has led to increased demand for nonprecious alternatives for widely practiced reactions such as the Suzuki-Miyaura coupling (SMC). Ni-catalyzed versions of this reaction have failed to achieve high reactivity with Lewis-basic arylboron nucleophiles, especially pinacolboron esters. We describe the development of (PPh

Biaryl phosphorinane ligands derived from addition of biaryl primary phosphines to trans,trans-dibenzylideneacetone (AlisonPhos and AliPhos) form highly active ligands for Pd-catalyzed coupling of ...

The preceding article described the development of the large-scale synthetic route to macrocycle 3 of glecaprevir (1), a potent HCV protease inhibitor. This article describes the development of the...

IL-36 cytokines are pro-inflammatory members of the IL-1 family that are upregulated in inflammatory disorders. Specifically, IL-36γ is highly expressed in active psoriatic lesions and can drive pro-inflammatory processes in 3D human skin equivalents supporting a role for this target in skin inflammation. Small molecule antagonists of interleukins have been historically challenging to generate. Nevertheless, we performed a small molecule high-throughput screen to identify IL-36 antagonists using a novel TR-FRET binding assay. Several compounds, including 2-oxypyrimidine containing structural analogs of the marketed endothelin receptor A antagonist Ambrisentan, were identified as hits from the screen. A-552 was identified as a the most potent antagonist of human IL-36γ, but not the closely related family member IL-36α, was capable of attenuating IL-36γ induced responses in mouse and human disease models. Additionally, x-ray crystallography studies identified key amino acid residues in the binding pocket present in human IL-36γ that are absent in human IL-36α. A-552 represents a first-in-class small molecule antagonist of IL-36 signaling that could be used as a chemical tool to further investigate the role of this pathway in inflammatory skin diseases such as psoriasis.

The tandem TUDOR domains present in the non-catalytic C-terminal half of the KDM4A, 4B and 4C enzymes play important roles in regulating their chromatin localizations and substrate specificities. They achieve this regulatory role by binding to different tri-methylated lysine residues on histone H3 (H3-K4me3, H3-K23me3) and histone H4 (H4-K20me3) depending upon the specific chromatin environment. In this work, we have used a 2D-NMR based fragment screening approach to identify a novel fragment (1a), which binds to the KDM4A-TUDOR domain and shows modest competition with H3-K4me3 binding in biochemical as well as in vitro cell based assays. A co-crystal structure of KDM4A TUDOR domain in complex with 1a shows that the fragment binds stereo-specifically to the methyl lysine binding pocket forming a network of strong hydrogen bonds and hydrophobic interactions. We anticipate that the fragment 1a can be further developed into a novel allosteric inhibitor of the KDM4 family of enzymes through targeting their C-terminal tandem TUDOR domain.

We report the preparation and dehydration of a cocrystal of caffeine and 2,4-dihydroxybenzoic acid. The dehydration of cocrystals of macro-dimensions results in destruction of crystal morphology; however, crystal morphology is retained when the cocrystal is reduced to nanometer-dimensions, despite a lack of pores to accommodate loss of water.

Download : Download high-res image (149KB) Download : Download full-size image Hepatitis C virus (HCV) nucleoside inhibitors have been a key focus of nearly 2 decades of HCV drug research due to a high barrier to drug resistance and pan-genotypic activity profile provided by molecules in this drug class. Our investigations focused on several potent 2′-halogenated uridine-based HCV polymerase inhibitors, resulting in the discovery of novel 2′-deoxy-2′-dihalo-uridine analogs that are potent inhibitors in replicon assays for all genotypes. Further studies to improve in vivo performance of these nucleoside inhibitors identified aminoisobutyric acid ethyl ester (AIBEE) phosphoramidate prodrugs 18a and 18c, which provide high levels of the active triphosphate in dog liver. AIBEE prodrug 18c was compared with sofosbuvir (1) by co-dosing both compounds by oral administration in dog (5 mg/kg each) and measuring liver concentrations of the active triphosphate metabolite at both 4 and 24 h post dosing. In this study, 18c provided liver triphosphate concentrations that were 6-fold higher than sofosbuvir (1) at both biopsy time points, suggesting that 18c could be a highly effective agent for treating HCV infected patients in the clinic.

Transient receptor potential vanilloid 3 (TRPV3) is a Ca(2+)- and Na(+)-permeable channel with a unique expression pattern. TRPV3 is found in both neuronal and non-neuronal tissues, including dorsal root ganglia, spinal cord, and keratinocytes. Recent studies suggest that TRPV3 may play a role in inflammation, pain sensation, and skin disorders. TRPV3 studies have been challenging, in part due to a lack of research tools such as selective antagonists. Herein, we provide the first detailed report on the development of potent and selective TRPV3 antagonists featuring a pyridinyl methanol moiety. Systematic optimization of pharmacological, physicochemical, and ADME properties of original lead 5a resulted in identification of a novel and selective TRPV3 antagonist 74a, which demonstrated a favorable preclinical profile in two different models of neuropathic pain as well as in a reserpine model of central pain.

Theophylline, a pharmaceutical model compound, was screened for cocrystal formation using nine (di)hydroxybenzoic acids as cocrystal formers, namely, 2-, 3-, 4-hydroxybenzoic- and 2,3-, 2,4-, 2,5-, 2,6-, 3,4-, and 3,5-dihydroxybenzoic acids. The experiments were conducted using an efficient, reliable, and fast screening method based on thermodynamically driven solution-mediated phase transformation and revealed the formation of eight cocrystals and one salt. The theophylline-based solids were identified using powder and structurally characterized via single-crystal X-ray diffraction. The obtained solids are sustained by theopylline-carboxylic acid heterosynthons, in addition to both theophylline and carboxylic acid homosynthons. The results are a part of a systematic study of xanthine-alkaloid cocrystals that aims to establish synthon hierarchies in cocrystals comprised of molecules with multiple hydrogen-bonding functional groups. Structural features and synthon hierachies are discussed and compared to t...

We apply crystal engineering principles to prepare organic co-crystals and salts of sulfadiazine and pyridines. Pyridines are molecular building blocks utilized in crystal engineering that can disrupt the hydrogen bonded (amidine) N–H···N (pyrimidine) dimer within the parent sulfa drug (SD) crystals, while providing access to both co-crystals and salts. We have synthesized four co-crystals and three salts of sulfadiazine involving N,N-dimethyl-4-aminopyridine, 4-aminopyridine, 4-picoline, 4,4′-bipyridine, (E)-1,2-bis(4-pyridyl)ethylene, 1,2-bis(4-pyridyl)acetylene, and 4-(pyridin-4-yl)piperazine. Single-crystal X-ray analyses reveal three hydrogen-bond motifs, namely, dyads, rings, and chains based involving either (amidine/aniline) N–H···N (pyridine/pyrimidine), (pyridinium) +N–H···N– (amidide), (aniline/piperazine) N–H···O2S (sulfoxide) interactions, or a combination thereof. The hydrogen-bond motifs are assigned as D11(2), R22(8), R22(20), C22(17), and C22(13) graph sets. An analysis of the Cambridge S...

A novel method for Pd-catalyzed triflination of aryl and heteroaryl triflates using NaSO2CF3 as the nucleophile is described. The combination of Pd2(dba)3 and RockPhos formed the most effective catalyst. A broad range of functional groups and heteroaromatic compounds were tolerated under the neutral reaction conditions. The order of reactivity ArOTf ≥ ArCl ≥ ArBr is consistent with transmetalation being a slow step of the reaction.

A novel method for Pd-catalyzed triflination of aryl and heteroaryl triflates using NaSO2CF3 as the nucleophile is described. The combination of Pd2(dba)3 and RockPhos formed the most effective catalyst. A broad range of functional groups and heteroaromatic compounds were tolerated under the neutral reaction conditions. The order of reactivity ArOTf ≥ ArCl ≥ ArBr is consistent with transmetalation being a slow step of the reaction.

A novel 4-aminocyclopentapyrrolidine series of N-type Ca(2+) channel blockers have been discovered. Enantioselective synthesis of the 4-aminocyclopentapyrrolidines was enabled using N-tert-butyl sulfinamide chemistry. SAR studies demonstrate selectivity over L-type Ca(2+) channels. N-type Ca(2+) channel blockade was confirmed using electrophysiological recording techniques. Compound 25 is an N-type Ca(2+) channel blocker that produces antinociception in inflammatory and nociceptive pain models without exhibiting cardiovascular or motor liabilities.

A cocrystal of caffeine (caf) and 2-hydroxy-1-naphthoic acid (2H1NA), namely, (caf)·(2H1NA), was discovered via a screening method based on solution-mediated phase transformation (SMPT). The components crystallize as a two-component hydrogen-bonded assembly involving both an intermolecular O–H···N and intramolecular O–H···O hydrogen bond. The assemblies stack parallel and offset. Crystal data: monoclinic P 21/n space group, a = 7.909(2) A, b = 15.275(5) A, c = 14.704(5) A, β = 103.66(1)°, Z = 4, V = 1726.1(9) A3, D c = 1.471 g/cm3 and R 1 = 0.081, wR 2 = 0.163. The cocrystal (caf)·(2H1NA) was also subjected to polymorph screening using 15 different solvents, with all resulting solids being identified as the original form. A cocrystal of caffeine and 2-hydroxy-1-naphthoic acid was discovered via a screening method and is shown to form a two-component hydrogen-bonded molecular assembly based on an intermolecular O–H⋯N and intramolecular O–H⋯O hydrogen bond.

Tautomerism is a phenomenon well know to most chemists but frequently forgotten when chemistry leaves the bench and enters the computational realm. Through the examination of several examples from the crystallographic literature it can be clearly demonstrated that the tautomeric state of a molecules can strongly affect its nature.

Benzothiadiazine inhibitors of the HCV NS5B RNA-dependent RNA polymerase are an important class of non-nucleoside inhibitors that have received considerable attention in the search for novel HCV therapeutics. Research in our laboratories has identified a novel series of tetracyclic benzothiadiazine inhibitors of HCV polymerase bearing a benzylamino substituent on the B-ring. Compounds in this series exhibit low-nanomolar activities in both genotypes 1a and 1b polymerase inhibition assays and subgenomic replicon assays. Optimization of pharmacokinetic properties in rat led to compound 30, which has good oral bioavailability (F = 56%) and a favorable tissue distribution drug profile, with high liver to plasma ratios. Compound 30 is a potent inhibitor in replicon assays, with EC(50) values of 10 and 6 nM against genotypes 1a and 1b, respectively.

Caffeine, a pharmaceutical model compound, generally forms cocrystals with carboxylic acids that involve an O−H···N hydrogen bond between the carboxylic acid group of the acid and the caffeine imidazole moiety. Such solids are typically based on a single heterosynthon. To examine the facility of introducing additional supramolecular heterosynthons to the caffeine-carboxylic-acid cocrystal system, structural isomers of aromatic carboxylic acids (i.e., hydroxy- and dihydroxybenzoic acids) with additional hydrogen-bonding functional groups (i.e., hydroxy group) were screened for cocrystal formation. For this purpose, a highly efficient screening method based on thermodynamically driven solution-mediated phase transformation was utilized. This method enabled the rapid discovery of nine new solid phases involving caffeine. These caffeine phases were identified using single-crystal X-ray diffraction and FT-IR spectroscopy as cocrystals based on 2-, 3-, 4-hydroxybenzoic- and 2,3-, 2,4-, 2,5-, 3,4-, and 3,5-dihyd...

The additions of various five-membered ring aminoheterocycles to α-cyanocinnamonitriles were studied. Regiochemistry of product formation can in most cases be controlled by choosing the appropriate electrophile. An α-cyanocinnamonitrile with an additional β-leaving group normally provides products arising from initial attack of the ring amino group, while exo attack predominates in the case of the parent α-cyanocinnamonitrile. Aminopyrazole and aminoindazole provide only exo products with either electrophile. Product assignments were made via X-ray and 2D NMR methods; these assignments serve as a benchmark to several literature references and to future investigations of conjugate additions of these nucleophiles.

[structure: see text]. We report a new methodology for the construction of novel and uniquely shaped 3-azabicyclo[4.2.0]octan-4-one derivatives by combining the Ugi multicomponent reaction with [2+2] enone-olefin photochemical transformations. The overall sequence is capable of creating up to five stereocenters; however, in most cases, only two diastereomers are observed.

A linear synthesis of the glucuronide metabolite of ABT-751 was replaced with a convergent synthesis that features direct glycosidic coupling between the aglycone and a trichloroacetimidate glucuronyl donor. Structural elucidation of a unique and unexpected difluoroboron complex of the desired glycosidic coupling product along with optimization of the synthetic steps is described.

Starting from a rapidly metabolized adamantane 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) inhibitor 22a, a series of E-5-hydroxy-2-adamantamine inhibitors, exemplified by 22d and (+/-)-22f, was discovered. Many of these compounds are potent inhibitors of 11beta-HSD1 and are selective over 11beta-HSD2 for multiple species (human, mouse, and rat), unlike other reported species-selective series. These compounds have good cellular potency and improved microsomal stability. Pharmacokinetic profiling in rodents indicated moderate to large volumes of distribution, short half-lives, and a pharmacokinetic species difference with the greatest exposure measured in rat with 22d. One hour postdose liver, adipose, and brain tissue 11beta-HSD1 inhibition was confirmed with (+/-)-22f in a murine ex vivo assay. Although 5,7-disubstitued-2-adamantamines provided greater stability, a single, E-5-position, polar functional group afforded inhibitors with the best combination of stability, potency, and selectivity. These results indicate that adamantane metabolic stabilization sufficient to obtain short-acting, potent, and selective 11beta-HSD1 inhibitors has been discovered.

One of the primary objectives in the design of protein inhibitors is to shape the three-dimensional structures of small molecules to be complementary to the binding site of a target protein. In the course of our efforts to discover potent inhibitors of Bcl-2 family proteins, we found a unique folded conformation adopted by tethered aromatic groups in the ligand that significantly enhanced binding affinity to Bcl-XL. This finding led us to design compounds that were biased by nonbonding interactions present in a urea tether to adopt this bioactive, folded motif. To characterize the key interactions that induce the desired conformational bias, a series of substituted N,N'-diarylureas were prepared and analyzed using X-ray crystallography and quantum mechanical calculations. Stabilizing pi-stacking interactions and destabilizing steric interactions were predicted to work in concert in two of the substitution patterns to promote the bioactive conformation as a global energy minimum and result in a high target binding affinity. Conversely, intramolecular hydrogen bonding present in the third substitution motif promotes a less active, extended conformer as the energetically favored geometry. These findings were corroborated when the inhibition constant of binding to Bcl-XL was determined for fully elaborated analogues bearing these structural motifs. Finally, we obtained the NMR solution structure of the disubstituted N,N'-diarylurea bound to Bcl-XL demonstrating the folded conformation of the urea motif engaged in extensive pi-interactions with the protein.

ABT-492 has been under development at Abbott Laboratories as a quinolone antibiotic. A convergent syntheses was utilized to prepare the compound on a multi-kilogram scale. Difficulties in isolation of intermediates were overcome by developing control of the physical forms. Examples of controlling the agglomeration, crystal habit, and polymorphism of intermediates and the API are described.

A stereoselective synthesis of the hydroxyethylene dipeptide isostere 1 is described. The route employs a substrate-directed kinetic protonation of an alpha/gamma-substituted lactone to afford the desired stereochemistry. A method for converting the diastereomerically enriched intermediate lactone to the ring-open form with retention of stereochemistry is demonstrated. A novel procedure for utilizing N,N-dibromo-5,5-dimethylhydantoin in Hofmann rearrangements is disclosed. This route was used to prepare amino alcohol 1, the core portion of the HIV protease inhibitor A-792611, in 46% yield from phenylalanine-derived epoxide 2.

A stereoselective synthesis of ABT-100 1 , a novel farnesyl transferase inhibitor, is described. The key step involves a stereoselective addition of the heterocyclic zinc reagent 10 to chiral α-keto ester 9 in >10:1 diastereoselectivity using menthol as the chiral auxiliary. Crystallization of the product as the dimeric zinc complex facilitates isolation of product in >99:1 dr. The biaryl linkage is formed by the use of a Suzuki coupling employing only 0.06 mol% of the catalyst. Coupling of the two fragments is accomplished using a SNAr reaction between diol 5 and arylfluoride 4 . The overall yield for the five step sequence is 37% on kilogram scale.

Fiduxosin (1) has been under development at Abbott Laboratories for the treatment of benign prostatic hyperplasia. A convergent strategy required methodologies for preparation of an enantiomericall...

4,5-Diaryl-1H-pyrazole-3-ol was utilized as a versatile template to synthesize several classes of compounds such as pyrazolo-oxazines 7, pyrazolo-benzooxazines 9, pyrazolo-oxazoles 10, and its analogues 11a-c as potential COX-2 inhibitors. Compounds 11b,c were successfully synthesized with use of pyridinium p-toluenesulfonate mediated cyclization of the ketal intermediate. Diaryl-pyrazolo-benzooxazepine analogues were synthesized by using Cu-mediated cyclization of the O-alkylated arylbromide intermediate. Arylsulfonamides were synthesized efficiently on a large scale with 4-[4-(4-fluorophenyl)-5-hydroxy-2H-pyrazol-3-yl]benzenesulfonamide 31 template readily synthesized from commercially available 4-sulfamoyl benzoic acid 29. The structure of a representative compound from each class was confirmed by X-ray crystallography. Selected compounds tested for inhibitory activity against COX-1 and COX-2 enzymes showed good selectivity for COX-2 versus COX-1 enzyme.

Two novel series of potent and selective FTase inhibitors have been synthesized using structure-based design. Medicinal chemistry efforts led to the discovery of compound 4e with potent cellular activity and good oral bioavailability in dog. A synthetic route toward novel heterocycles 1,5-dimethyl-6-oxo-4-aryl-1,6-dihydro-pyridine-2-carbonitrile was established. The structure of compound 5c was confirmed by X-ray crystallography.

Structure-activity studies were performed on the alpha(1A)-adrenoceptor (AR) selective agonist N-[5-(1H-imidazol-4-yl)-5,6,7,8-tetrahydro-1-naphthalenyl]methanesulfonamide (4). Compounds were evaluated for binding activity at the alpha(1A), alpha(1b), alpha(1d), alpha(2a), and alpha(2B) subtypes. Functional activity in tissues containing the alpha(1A) (rabbit urethra), alpha(1B) (rat spleen), alpha(1D) (rat aorta), and alpha(2A) (rat prostatic vas deferens) was also evaluated. A dog in vivo model simultaneously measuring intraurethral pressure (IUP) and mean arterial pressure (MAP) was used to assess the uroselectivity of the compounds. Many of the compounds that were highly selective in vitro for the alpha(1A)-AR subtype were also more uroselective in vivo for increasing IUP over MAP than the nonselective alpha(1)-agonists phenylpropanolamine (PPA) (1) and ST-1059 (2, the active metabolite of midodrine), supporting the hypothesis that greater alpha(1A) selectivity would reduce cardiovascular side effects. However, the data also support a prominent role of the alpha(1A)-AR subtype in the control of MAP.

Structure−activity relationships were investigated on a novel series of sulfonyldihydropyridine-containing KATP openers. Ring sizes, absolute stereochemistry, and aromatic substitution were evaluated for KATP activity in guinea pig bladder cells using a fluorescence-based membrane potential assay and in a pig bladder strip assay. The inhibition of spontaneous bladder contractions in vitro was also examined for a select group of compounds. All compounds studied showed greater potency to inhibit spontaneous bladder contractions relative to their potencies to inhibit contractions elicited by electrical stimulation. In an anesthetized pig model of myogenic bladder overactivity, compound 14 and (−)-cromakalim 1 were found to inhibit spontaneous bladder contractions in vivo at plasma concentrations lower than those that affected hemodynamic parameters. Compound 14 showed approximately 5-fold greater selectivity than 1 in vivo and supports the concept that bladder-selective KATP channel openers may have utility ...

Purpose. In the summer of 1998, Norvir semi-solid capsules supplies were threatened as a result of a new much less soluble crystal form of ritonavir. This report provides characterization of the two polymorphs and the structures and hydrogen bonding network for each form.

Ritonavir (Kempf, D. J.; Marsh, K. C., Denissen, J. F.; McDonald, E.; Vasavanonda, S.; Flentge, C. A.; Green, B. E.; Fino, L.; Park, C. H.; Kong, X. P.; Wideburg, N. E.; Saldivar, A.; Ruitz, L.; Kati, W. M.; Sham, H. L.; Robins, T.; Stewart, K. D.; Hsu, A.; Plattner, J. J.; Leonard, J. M.; Norbeck, D. W. Proc. Natl. Acad. Sci. U.S.A. 1995, 92, 2484) is Abbott's novel protease inhibitor, for human immunodeficiency virus (HIV), the causative organism of acquired immunodeficiency syndrome (AIDS). It is marketed as Norvir. From the discovery of ritonavir until the new drug application (NDA) filing, only one crystalline form was known to exist. Attempts to identify other possible crystal forms were unsuccessful. Two years after the launch of Norvir to the market, some lots of Norvir capsules failed a dissolution specification. Investigation of this phenomena revealed the existence of a crystal form of ritonavir other than the one already known (Form I). This new crystal form was designated as Form II. The two ...

The Ollis–Sweeney ammonium ylid rearrangement has been effectively utilized to provide access to hitherto unknown hybrid privileged structural motifs. The rearrangement of didehydropiperidinium salts containing tethered olefins at the 4-position afforded, after subsequent ring closing metathesis, novel spirocyclic scaffolds suitable for further elaboration and incorporation of final structures into HTS sets.

The 11,12-cyclic carbazate of 3-keto-6-O-methylerythromycin A (4) was prepared. This compound shows in vitro antibacterial activity comparable to erythromycin A (1) against erythromycin-susceptible organisms and increased activity against some erythromycin-resistant organisms. Using 4 as a lead, a series of analogues was prepared by acylation or alkylation of the carbazate nitrogen. Several of the N-alkylated derivatives showed dramatically improved antibacterial activity against both susceptible and resistant organisms as compared to erythromycin A.

The novel calcineurin inhibitor, dibefurin, has been isolated from the fungal culture AB 1650I-759. The isolation was bioactivity-directed fractionation using an assay which measures the phosphatase activity of calcineurin. The compound was purified by countercurrent, reverse phase and gel filtration chromatographies. Several studies, including crystallographic, NMR and MS, revealed that dibefurin is a novel dimeric compound of a unique structural type.

GT-2331 is a potent histamine H(3) antagonist which has entered clinical trials. Efficient multigram syntheses of this compound and its enantiomer are described. The literature reports that GT-2331 is the dextrorotatory (+), more potent, enantiomer of 4-[2-(5,5-dimethylhex-1-ynyl)cyclopropyl]-1H-imidazole with the absolute configuration of (1R,2R)-1. However, we found that the dextrorotatory, more potent, enantiomer of 4-[2-(5,5-dimethylhex-1-ynyl)cyclopropyl]-1H-imidazole has the (1S,2S) absolute configuration. We suggest a reconsideration of the absolute configuration of GT-2331.

A novel 4-aminocyclopentapyrrolidine series of N-type Ca(2+) channel blockers have been discovered. Enantioselective synthesis of the 4-aminocyclopentapyrrolidines was enabled using N-tert-butyl sulfinamide chemistry. SAR studies demonstrate selectivity over L-type Ca(2+) channels. N-type Ca(2+) channel blockade was confirmed using electrophysiological recording techniques. Compound 25 is an N-type Ca(2+) channel blocker that produces antinociception in inflammatory and nociceptive pain models without exhibiting cardiovascular or motor liabilities.

The crystal structures of five methylene substituted crown ether compounds were investigated. [Na(OH2)(methylene-16-crown-5)]I is orthorhombic, P212121 with a = 7.920(9), b = 10.787(3), c = 20.870(5)A, and Dcalc = 1.54 g cm−3 for Z = 4. The sodium cation is coordinated to all five etheric oxygen atoms and a water molecule giving it a coordination number of six. [Na(NO2)(methylene-16-crown-5)]·0.5(H2O) is monoclinic, P21/n with a = 20.566(6), b = 8.605(9), c = 20.821(7)A, β = 115.66(3)·, and Dcalc = 130 g cm−3 for Z = 8. Each sodium cation is seven-coordinate, coordinated to all five etheric oxygen atoms and a bidentate nitrite anion. One crown molecule is severely disordered. The macrocycles in both methylene-16-crown-5 structures have essentially the same conformations. 3,16-dimethylene-26-crown-8 is orthorhombic, Pccn with a = 18.061(4), b = 14.320(4), c = 8.659(7)A, and Dcalc = 1.20 g cm−3 for Z = 4. The crown ether has an elongated cavity generated by a series of six consecutive anti torsion ...

Reaction of the C-7 hydroryl group on the 9-dihydrotaxane skeleton with triflic anhydride causes a major skeletal rearrangement to occur leading to contraction of ring B. In addition the formation of a ring C-fused cyclopropane structure occurs. The requisite C-13 phenylisoserinate side chins are appended via an initial deacylation of the C-13 acetate followed by reacylation and deprotection. These rearranged compounds show very similar structural features with the parent 9-dihydrotaxane skeleton and also retain biological activity

The regiospecific synthesis of highly substituted 2-pyridylindoles has been accomplished via a three step reaction sequence which involves the unique formation of the synthetically flexible pyridine intermediate 2 .

Ascomycin (1) is a close analogue of the immunosuppressant FK-506 (2) which differs slightly in the side chain at position 21 (ethyl vs allyl). Structurally unique ascomycin and FK-506 are the subjects of intense chemical research because of their application in organ transplantation and autoimmune disease. We have been interested in studying the effect of structural modification and conformational change on biological activity. This paper reports the fermentation and structural determination of ascomycin as well as the synthesis and structure confirmation of a series of pyrazole analogues (3 and 4) derived from ascomycin.