All Publications

  • Brain-penetrant cyanoindane and cyanotetralin inhibitors of G2019S-LRRK2 kinase activity BIOORGANIC & MEDICINAL CHEMISTRY LETTERS Garofalo, A. W., Schwarz, J., Zobel, K., Beato, C., Bernardi, S., Budassi, F., Caberlotto, L., Gao, P., Griffante, C., Liu, X., Migliore, M., Qiao, F., Sabbatini, F., Sava, A., Zhang, M., Carlisle, H. J. 2023; 95: 129487


    The G2019S variant of LRRK2, which causes an increase in kinase activity, is associated with the occurrence of Parkinson's disease (PD). Potent, mutation-selective, and brain penetrant inhibitors of LRRK2 can suppress the biological effects specific to G2019S-LRRK2 that cause pathogenicity. We report the discovery of a series of cyanoindane and cyanotetralin kinase inhibitors culminating in compound 34 that demonstrated selective inhibition of phosphorylation of LRRK2 in the mouse brain. These novel inhibitors may further enable the precision medicine path for future PD therapeutics.

    View details for DOI 10.1016/j.bmcl.2023.129487

    View details for Web of Science ID 001082766700001

    View details for PubMedID 37734423

  • Selective Inhibitors of G2019S-LRRK2 Kinase Activity. Journal of medicinal chemistry Garofalo, A. W., Bright, J., De Lombaert, S., Toda, A. M., Zobel, K., Andreotti, D., Beato, C., Bernardi, S., Budassi, F., Caberlotto, L., Gao, P., Griffante, C., Liu, X., Mengatto, L., Migliore, M., Sabbatini, F. M., Sava, A., Serra, E., Vincetti, P., Zhang, M., Carlisle, H. J. 2020; 63 (23): 14821-14839


    Pathogenic variants in the leucine-rich repeat kinase 2 (LRRK2) gene have been identified that increase the risk for developing Parkinson's disease in a dominantly inherited fashion. These pathogenic variants, of which G2019S is the most common, cause abnormally high kinase activity, and compounds that inhibit this activity are being pursued as potentially disease-modifying therapeutics. Because LRRK2 regulates important cellular processes, developing inhibitors that can selectively target the pathogenic variant while sparing normal LRRK2 activity could offer potential advantages in heterozygous carriers. We conducted a high-throughput screen and identified a single selective compound that preferentially inhibited G2019S-LRRK2. Optimization of this scaffold led to a series of novel, potent, and highly selective G2019S-LRRK2 inhibitors.

    View details for DOI 10.1021/acs.jmedchem.0c01243

    View details for PubMedID 33197196

  • Site-Specific Tandem Knoevenagel Condensation-Michael Addition To Generate Antibody-Drug Conjugates. ACS medicinal chemistry letters Kudirka, R. A., Barfield, R. M., McFarland, J. M., Drake, P. M., Carlson, A., Bañas, S., Zmolek, W., Garofalo, A. W., Rabuka, D. 2016; 7 (11): 994-998


    Expanded ligation techniques are sorely needed to generate unique linkages for the growing field of functionally enhanced proteins. To address this need, we present a unique chemical ligation that involves the double addition of a pyrazolone moiety with an aldehyde-labeled protein. This ligation occurs via a tandem Knoevenagel condensation-Michael addition. A pyrazolone reacts with an aldehyde to generate an enone, which undergoes subsequent attack by a second pyrazolone to generate a bis-pyrazolone species. This rapid and facile ligation technique is performed under mild conditions in the absence of catalyst to generate new architectures that were previously inaccessible via conventional ligation reactions. Using this unique ligation, we generated three site-specifically labeled antibody-drug conjugates (ADCs) with an average of four drugs to one antibody. The in vitro and in vivo efficacies along with pharmacokinetic data of the site-specific ADCs are reported.

    View details for DOI 10.1021/acsmedchemlett.6b00253

    View details for PubMedID 27882197

    View details for PubMedCentralID PMC5108035

  • Generating site-specifically modified proteins via a versatile and stable nucleophilic carbon ligation. Chemistry & biology Kudirka, R., Barfield, R. M., McFarland, J., Albers, A. E., de Hart, G. W., Drake, P. M., Holder, P. G., Banas, S., Jones, L. C., Garofalo, A. W., Rabuka, D. 2015; 22 (2): 293-8


    There is a need for facile chemistries that allow for chemo- and regioselectivity in bioconjugation reactions. To address this need, we are pioneering site-specific bioconjugation methods that use formylglycine as a bioorthogonal handle on a protein surface. Here we introduce aldehyde-specific bioconjugation chemistry, the trapped-Knoevenagel ligation. The speed and stability of the trapped-Knoevenagel ligation further advances the repertoire of aldehyde-based bioconjugations and expands the toolbox for site-specific protein modifications. The trapped-Knoevenagel ligation reaction can be run at near neutral pH in the absence of catalysts to produce conjugates that are stable under physiological conditions. Using this new ligation, we generated an antibody-drug conjugate that demonstrates excellent efficacy in vitro and in vivo.

    View details for DOI 10.1016/j.chembiol.2014.11.019

    View details for PubMedID 25619935

  • Exploring the effects of linker composition on site-specifically modified antibody-drug conjugates. European journal of medicinal chemistry Albers, A. E., Garofalo, A. W., Drake, P. M., Kudirka, R., de Hart, G. W., Barfield, R. M., Baker, J., Banas, S., Rabuka, D. 2014; 88: 3-9


    In the context of antibody-drug conjugates (ADCs), noncleavable linkers provide a means to deliver cytotoxic small molecules to cell targets while reducing systemic toxicity caused by nontargeted release of the free drug. Additionally, noncleavable linkers afford an opportunity to change the chemical properties of the small molecule to improve potency or diminish affinity for multidrug transporters, thereby improving efficacy. We employed the aldehyde tag coupled with the hydrazino-iso-Pictet-Spengler (HIPS) ligation to generate a panel of site-specifically conjugated ADCs that varied only in the noncleavable linker portion. The ADC panel comprised antibodies carrying a maytansine payload ligated through one of five different linkers. Both the linker-maytansine constructs alone and the resulting ADC panel were characterized in a variety of in vitro and in vivo assays measuring biophysical and functional properties. We observed that slight differences in linker design affected these parameters in disparate ways, and noted that efficacy could be improved by selecting for particular attributes. These studies serve as a starting point for the exploration of more potent noncleavable linker systems.

    View details for DOI 10.1016/j.ejmech.2014.08.062

    View details for PubMedID 25176286

  • Aldehyde tag coupled with HIPS chemistry enables the production of ADCs conjugated site-specifically to different antibody regions with distinct in vivo efficacy and PK outcomes. Bioconjugate chemistry Drake, P. M., Albers, A. E., Baker, J., Banas, S., Barfield, R. M., Bhat, A. S., de Hart, G. W., Garofalo, A. W., Holder, P., Jones, L. C., Kudirka, R., McFarland, J., Zmolek, W., Rabuka, D. 2014; 25 (7): 1331-41


    It is becoming increasingly clear that site-specific conjugation offers significant advantages over conventional conjugation chemistries used to make antibody-drug conjugates (ADCs). Site-specific payload placement allows for control over both the drug-to-antibody ratio (DAR) and the conjugation site, both of which play an important role in governing the pharmacokinetics (PK), disposition, and efficacy of the ADC. In addition to the DAR and site of conjugation, linker composition also plays an important role in the properties of an ADC. We have previously reported a novel site-specific conjugation platform comprising linker payloads designed to selectively react with site-specifically engineered aldehyde tags on an antibody backbone. This chemistry results in a stable C-C bond between the antibody and the cytotoxin payload, providing a uniquely stable connection with respect to the other linker chemistries used to generate ADCs. The flexibility and versatility of the aldehyde tag conjugation platform has enabled us to undertake a systematic evaluation of the impact of conjugation site and linker composition on ADC properties. Here, we describe the production and characterization of a panel of ADCs bearing the aldehyde tag at different locations on an IgG1 backbone conjugated using Hydrazino-iso-Pictet-Spengler (HIPS) chemistry. We demonstrate that in a panel of ADCs with aldehyde tags at different locations, the site of conjugation has a dramatic impact on in vivo efficacy and pharmacokinetic behavior in rodents; this advantage translates to an improved safety profile in rats as compared to a conventional lysine conjugate.

    View details for DOI 10.1021/bc500189z

    View details for PubMedID 24924618

    View details for PubMedCentralID PMC4215875

  • Triazolopyridazine LRRK2 kinase inhibitors BIOORGANIC & MEDICINAL CHEMISTRY LETTERS Franzini, M., Ye, X. M., Adler, M., Aubele, D. L., Garofalo, A. W., Gauby, S., Goldbach, E., Probst, G. D., Quinn, K. P., Santiago, P., Sham, H. L., Tam, D., Anh Truong, A., Ren, Z. 2013; 23 (7): 1967-1973


    Leucine-rich repeat kinase 2 (LRRK2) has been implicated in the pathogenesis of Parkinson's disease (PD). Inhibition of LRRK2 kinase activity is a therapeutic approach that may lead to new treatments for PD. Herein we report the discovery of a series of [1,2,4]triazolo[4,3-b]pyridazines that are potent against both wild-type and mutant LRRK2 kinase activity in biochemical assays and show an unprecedented selectivity towards the G2019S mutant. A structural rational for the observed selectivity is proposed.

    View details for DOI 10.1016/j.bmcl.2013.02.043

    View details for Web of Science ID 000316642900010

  • Discovery of 4-alkylamino-7-aryl-3-cyanoquinoline LRRK2 kinase inhibitors. Bioorganic & medicinal chemistry letters Garofalo, A. W., Adler, M., Aubele, D. L., Brigham, E. F., Chian, D., Franzini, M., Goldbach, E., Kwong, G. T., Motter, R., Probst, G. D., Quinn, K. P., Ruslim, L., Sham, H. L., Tam, D., Tanaka, P., Truong, A. P., Ye, X. M., Ren, Z. 2013; 23 (7): 1974-7


    Mutations in leucine-rich repeat kinase 2 (LRRK2) are associated with familial Parkinson's disease (PD). The kinase activity of this complex protein is increased by pathogenic mutations. Inhibition of LRRK2 kinase activity has therefore emerged as a promising approach for the treatment of PD. Herein we report our findings on a series of 4-alkylamino-7-aryl-3-cyanoquinolines that exhibit kinase inhibitory activity against both wild type and G2019S mutant LRRK2. Activity was determined in both biochemical and cellular assays. Compound 14 was further evaluated in an in vivo pharmacodynamic study and found to significantly inhibit Ser935 phosphorylation after oral dosing.

    View details for DOI 10.1016/j.bmcl.2013.02.041

    View details for PubMedID 23453068

  • Novel cinnoline-based inhibitors of LRRK2 kinase activity. Bioorganic & medicinal chemistry letters Garofalo, A. W., Adler, M., Aubele, D. L., Bowers, S., Franzini, M., Goldbach, E., Lorentzen, C., Neitz, R. J., Probst, G. D., Quinn, K. P., Santiago, P., Sham, H. L., Tam, D., Truong, A. P., Ye, X. M., Ren, Z. 2013; 23 (1): 71-4


    Leucine rich repeat kinase 2 (LRRK2) has been implicated in the pathogenesis of Parkinson's disease (PD). Inhibition of LRRK2 kinase activity is a therapeutic approach that may lead to new treatments for PD. Herein we report the discovery of a series of cinnoline-3-carboxamides that are potent against both wild-type and mutant LRRK2 kinase activity in biochemical assays. These compounds are also shown to be potent inhibitors in a cellular assay and to have good to excellent CNS penetration.

    View details for DOI 10.1016/j.bmcl.2012.11.021

    View details for PubMedID 23219325

  • Synthesis of novel tetrahydro-1H-pyrazolo[4,3-c]pyridines via intramolecular nitrilimine cycloaddition. Chemical & pharmaceutical bulletin Garofalo, A. W., Jagodzinski, J. J., Konradi, A. W., Ng, R. A., Semko, C. M., Sham, H. L., Sun, M., Ye, X. M. 2012; 60 (8): 1063-6


    The preparation of novel tetrahydro-1H-pyrazolo[4,3-c]pyridines is reported. Pivotal to the synthesis of these compounds was the development of mild reaction conditions to generate a highly functionalized nitrilimine capable of undergoing an intramolecular cycloaddition with a tethered alkyne. The desired cycloadduct was formed as an equal mixture of diastereomers.

    View details for DOI 10.1248/cpb.c110498

    View details for PubMedID 22863711

  • Design, synthesis and structure-activity relationship of novel [3.3.1] bicyclic sulfonamide-pyrazoles as potent gamma-secretase inhibitors BIOORGANIC & MEDICINAL CHEMISTRY LETTERS Aubele, D. L., Truong, A. P., Dressen, D. B., Probst, G. D., Bowers, S., Mattson, M. N., Semko, C. M., Sun, M., Garofalo, A. W., Konradi, A. W., Sham, H. L., Zmolek, W., Wong, K., Goldbach, E., Quinn, K. P., Sauer, J., Brigham, E. F., Wallace, W., Nguyen, L., Bova, M. P., Hemphill, S. S., Basi, G. 2011; 21 (19): 5791-5794


    The structure-activity relationship (SAR) of a novel, potent and metabolically stable series of sulfonamide-pyrazoles that attenuate β-amyloid peptide synthesis via γ-secretase inhibition is detailed herein. Sulfonamide-pyrazoles that are efficacious in reducing the cortical Aβx-40 levels in FVB mice via a single PO dose, as well as sulfonamide-pyrazoles that exhibit selectivity for inhibition of APP versus Notch processing by γ-secretase, are highlighted.

    View details for DOI 10.1016/j.bmcl.2011.08.008

    View details for Web of Science ID 000294714400028

    View details for PubMedID 21885276

  • Amyloid precursor protein selective gamma-secretase inhibitors for treatment of Alzheimer's disease. Alzheimer's research & therapy Basi, G. S., Hemphill, S., Brigham, E. F., Liao, A., Aubele, D. L., Baker, J., Barbour, R., Bova, M., Chen, X. H., Dappen, M. S., Eichenbaum, T., Goldbach, E., Hawkinson, J., Lawler-Herbold, R., Hu, K., Hui, T., Jagodzinski, J. J., Keim, P. S., Kholodenko, D., Latimer, L. H., Lee, M., Marugg, J., Mattson, M. N., McCauley, S., Miller, J. L., Motter, R., Mutter, L., Neitzel, M. L., Ni, H., Nguyen, L., Quinn, K., Ruslim, L., Semko, C. M., Shapiro, P., Smith, J., Soriano, F., Szoke, B., Tanaka, K., Tang, P., Tucker, J. A., Ye, X. M., Yu, M., Wu, J., Xu, Y. Z., Garofalo, A. W., Sauer, J. M., Konradi, A. W., Ness, D., Shopp, G., Pleiss, M. A., Freedman, S. B., Schenk, D. 2010; 2 (6): 36


    Inhibition of gamma-secretase presents a direct target for lowering Aβ production in the brain as a therapy for Alzheimer's disease (AD). However, gamma-secretase is known to process multiple substrates in addition to amyloid precursor protein (APP), most notably Notch, which has limited clinical development of inhibitors targeting this enzyme. It has been postulated that APP substrate selective inhibitors of gamma-secretase would be preferable to non-selective inhibitors from a safety perspective for AD therapy.In vitro assays monitoring inhibitor potencies at APP γ-site cleavage (equivalent to Aβ40), and Notch ε-site cleavage, in conjunction with a single cell assay to simultaneously monitor selectivity for inhibition of Aβ production vs. Notch signaling were developed to discover APP selective gamma-secretase inhibitors. In vivo efficacy for acute reduction of brain Aβ was determined in the PDAPP transgene model of AD, as well as in wild-type FVB strain mice. In vivo selectivity was determined following seven days x twice per day (b.i.d.) treatment with 15 mg/kg/dose to 1,000 mg/kg/dose ELN475516, and monitoring brain Aβ reduction vs. Notch signaling endpoints in periphery.The APP selective gamma-secretase inhibitors ELN318463 and ELN475516 reported here behave as classic gamma-secretase inhibitors, demonstrate 75- to 120-fold selectivity for inhibiting Aβ production compared with Notch signaling in cells, and displace an active site directed inhibitor at very high concentrations only in the presence of substrate. ELN318463 demonstrated discordant efficacy for reduction of brain Aβ in the PDAPP compared with wild-type FVB, not observed with ELN475516. Improved in vivo safety of ELN475516 was demonstrated in the 7d repeat dose study in wild-type mice, where a 33% reduction of brain Aβ was observed in mice terminated three hours post last dose at the lowest dose of inhibitor tested. No overt in-life or post-mortem indications of systemic toxicity, nor RNA and histological end-points indicative of toxicity attributable to inhibition of Notch signaling were observed at any dose tested.The discordant in vivo activity of ELN318463 suggests that the potency of gamma-secretase inhibitors in AD transgenic mice should be corroborated in wild-type mice. The discovery of ELN475516 demonstrates that it is possible to develop APP selective gamma-secretase inhibitors with potential for treatment for AD.

    View details for DOI 10.1186/alzrt60

    View details for PubMedID 21190552

    View details for PubMedCentralID PMC3031881

  • Discovery of a novel sulfonamide-pyrazolopiperidine series as potent and efficacious gamma-secretase inhibitors (Part II) BIOORGANIC & MEDICINAL CHEMISTRY LETTERS Ye, X. M., Konradi, A. W., Smith, J., Aubele, D. L., Garofalo, A. W., Marugg, J., Neitzel, M. L., Semko, C. M., Sham, H. L., Sun, M., Truong, A. P., Wu, J., Zhang, H., Goldbach, E., Sauer, J., Brigham, E. F., Bova, M., Basi, G. S. 2010; 20 (12): 3502-3506


    Significant improvement in metabolic stability on the pyrazolopiperidine scaffold over the original series were achieved and this stability improvement translated in an improved in vivo efficacy.

    View details for DOI 10.1016/j.bmcl.2010.04.148

    View details for Web of Science ID 000278208200009

    View details for PubMedID 20529683

  • Discovery of a novel sulfonamide-pyrazolopiperidine series as potent and Efficacious gamma-Secretase Inhibitors BIOORGANIC & MEDICINAL CHEMISTRY LETTERS Ye, X. M., Konradi, A. W., Smith, J., Xu, Y., Dressen, D., Garofalo, A. W., Marugg, J., Sham, H. L., Truong, A. P., Jagodzinski, J., Pleiss, M., Zhang, H., Goldbach, E., Sauer, J., Brigham, E., Bova, M., Basi, G. S. 2010; 20 (7): 2195-2199


    Discovery of a series of pyrazolopiperidine sulfonamide based gamma-secretase inhibitors and its SAR evolution is described. Significant increases in APP potency on the pyrazolopiperidine scaffold over the original N-bicyclic sulfonamide scaffold were achieved and this potency increase translated in an improved in vivo efficacy.

    View details for DOI 10.1016/j.bmcl.2010.02.039

    View details for Web of Science ID 000275805900031

    View details for PubMedID 20207136

  • Discovery of sulfonamide-pyrazole gamma-secretase inhibitors. Bioorganic & medicinal chemistry letters Mattson, M. N., Neitzel, M. L., Quincy, D. A., Semko, C. M., Garofalo, A. W., Keim, P. S., Konradi, A. W., Pleiss, M. A., Sham, H. L., Brigham, E. F., Goldbach, E. G., Zhang, H., Sauer, J. M., Basi, G. S. 2010; 20 (7): 2148-50


    Utilizing a pharmacophore hypothesis, previously described gamma-secretase inhibiting HTS hits were evolved into novel tricyclic sulfonamide-pyrazoles, with high in vitro potency, good brain penetration, low metabolic stability, and high clearance.

    View details for DOI 10.1016/j.bmcl.2010.02.050

    View details for PubMedID 20206516

  • N-Bridged bicyclic sulfonamides as inhibitors of gamma-secretase BIOORGANIC & MEDICINAL CHEMISTRY LETTERS Bowers, S., Probst, G. D., Truong, A. P., Hom, R. K., Konradi, A. W., Sham, H. L., Garofalo, A. W., Wong, K., Goldbach, E., Quinn, K. P., Sauer, J., Wallace, W., Nguyen, L., Hemphill, S. S., Bova, M. P., Basi, G. S. 2009; 19 (24): 6952-6956


    The structural modification of a series of [3.3.1] bicyclic sulfonamide based gamma-secretase inhibitors is described. Appropriate substitution on the bicyclic scaffold provides a significant increase in the metabolic stability of the compounds resulting in an improved in vivo metabolic profile.

    View details for DOI 10.1016/j.bmcl.2009.10.060

    View details for Web of Science ID 000271724200028

    View details for PubMedID 19879755

  • Design, synthesis, and structure-activity relationship of novel orally efficacious pyrazole/sulfonamide based dihydroquinoline gamma-secretase inhibitors BIOORGANIC & MEDICINAL CHEMISTRY LETTERS Truong, A. P., Aubele, D. L., Probst, G. D., Neitzel, M. L., Semko, C. M., Bowers, S., Dressen, D., Hom, R. K., Konradi, A. W., Sham, H. L., Garofalo, A. W., Keim, P. S., Wu, J., Dappen, M. S., Wong, K., Goldbach, E., Quinn, K. P., Sauer, J., Brigham, E. F., Wallace, W., Nguyen, L., Hemphill, S. S., Bova, M. P., Basi, G. 2009; 19 (17): 4920-4923


    In this Letter, we report our strategy to design potent and metabolically stable gamma-secretase inhibitors that are efficacious in reducing the cortical Abetax-40 levels in FVB mice via a single PO dose.

    View details for DOI 10.1016/j.bmcl.2009.07.092

    View details for Web of Science ID 000268863800004

    View details for PubMedID 19660943

  • Patents targeting γ-secretase inhibition and modulation for the treatment of Alzheimer's disease:: 2004-2008 EXPERT OPINION ON THERAPEUTIC PATENTS Garofalo, A. W. 2008; 18 (7): 693-703
  • Preparation and optimization of a series of 3-carboxamido-5-phenacylaminopyrazole bradykinin B1 receptor antagonists. Journal of medicinal chemistry Dressen, D., Garofalo, A. W., Hawkinson, J., Hom, D., Jagodzinski, J., Marugg, J. L., Neitzel, M. L., Pleiss, M. A., Szoke, B., Tung, J. S., Wone, D. W., Wu, J., Zhang, H. 2007; 50 (21): 5161-7


    The B1 receptor is an attractive target for the treatment of pain and inflammation. A series of 3-carboxamido-5-phenacylamino pyrazole B1 receptor antagonists are described that exhibit good potency against B1 and high selectivity over B2. Initially, N-unsubstituted pyrazoles were studied, but these compounds suffered from extensive glucuronidation in primates. This difficulty could be surmounted by the use of N-substituted pyrazoles. Optimization efforts culminated in compound 41, which has high receptor potency and metabolic stability.

    View details for DOI 10.1021/jm051292n

    View details for PubMedID 17880055

  • Pharmacological, pharmacokinetic, and primate analgesic efficacy profile of the novel bradykinin B1 Receptor antagonist ELN441958. The Journal of pharmacology and experimental therapeutics Hawkinson, J. E., Szoke, B. G., Garofalo, A. W., Hom, D. S., Zhang, H., Dreyer, M., Fukuda, J. Y., Chen, L., Samant, B., Simmonds, S., Zeitz, K. P., Wadsworth, A., Liao, A., Chavez, R. A., Zmolek, W., Ruslim, L., Bova, M. P., Holcomb, R., Butelman, E. R., Ko, M. C., Malmberg, A. B. 2007; 322 (2): 619-30


    The bradykinin B(1) receptor plays a critical role in chronic pain and inflammation, although efforts to demonstrate efficacy of receptor antagonists have been hampered by species-dependent potency differences, metabolic instability, and low oral exposure of current agents. The pharmacology, pharmacokinetics, and analgesic efficacy of the novel benzamide B(1) receptor antagonist 7-chloro-2-[3-(9-pyridin-4-yl-3,9-diazaspiro[5.5]undecanecarbonyl)phenyl]-2,3-dihydro-isoindol-1-one (ELN441958) is described. ELN441958 competitively inhibited the binding of the B(1) agonist ligand [(3)H]desArg(10)-kallidin ([(3)H]DAKD) to IMR-90 human fibroblast membranes with high affinity (K(i) = 0.26 +/- 0.02 nM). ELN441958 potently antagonized DAKD (but not bradykinin)-induced calcium mobilization in IMR-90 cells, indicating that it is highly selective for B(1) over B(2) receptors. Antagonism of agonist-induced calcium responses at B(1) receptors from different species indicated that ELN441958 is selective for primate over rodent B(1) receptors with a rank order potency (K(B), nanomolar) of human (0.12 +/- 0.02) approximately rhesus monkey (0.24 +/- 0.01) > rat (1.5 +/- 0.4) > mouse (14 +/- 4). ELN441958 had good permeability and metabolic stability in vitro consistent with high oral exposure and moderate plasma half-lives in rats and rhesus monkeys. Because ELN441958 is up to 120-fold more potent at primate than at rodent B(1) receptors, it was evaluated in a primate pain model. ELN441958 dose-dependently reduced carrageenan-induced thermal hyperalgesia in a rhesus monkey tail-withdrawal model, with an ED(50) approximately 3 mg/kg s.c. Naltrexone had no effect on the antihyperalgesia produced by ELN441958, indicating a lack of involvement of opioid receptors. ELN441958 is a novel small molecule bradykinin B(1) receptor antagonist exhibiting high oral bioavailability and potent systemic efficacy in rhesus monkey inflammatory pain.

    View details for DOI 10.1124/jpet.107.120352

    View details for PubMedID 17470643

  • Optimizing phenylethylphosphonamidates for the inhibition of prostate-specific membrane antigen. Bioorganic & medicinal chemistry Wone, D. W., Rowley, J. A., Garofalo, A. W., Berkman, C. E. 2006; 14 (1): 67-76


    A series of eight N-2-phenylethylphosphonyl derivatives of glutamic acid was prepared to determine if the inhibitory potency of a phenylethylphosphonyl derivative of glutamic acid against prostate-specific membrane antigen (PSMA) could be improved through rational substitutions on the phenyl ring. The design of these eight analogs was based upon the Topliss batchwise approach. Of the inhibitors from the first generation, the 3,4-dichlorophenyl analog exhibited the greatest improvement over the lead compound which was an unsubstituted phenyl derivative, while the 4-methoxyphenyl analog was essentially void of inhibitory potency against PSMA in single-dose studies. From the potency ranking order of the first generation, the parameter most important to the pharmacophore was determined to be pi + sigma. Attempts to optimize further the potency of inhibitors by preparing a second generation of compounds did not result in structures with greater potency than that of the 3,4-dichlorophenyl analog from the first generation. Based upon K(i) values, the 3,4-dichlorophenyl analog represented a potency improvement of nearly one order of magnitude. These results confirm further the usefulness of the Topliss approach to analog development when large library synthesis cannot be achieved readily.

    View details for DOI 10.1016/j.bmc.2005.07.056

    View details for PubMedID 16154750

  • A series of C-terminal amino alcohol dipeptide A beta inhibitors. Bioorganic & medicinal chemistry letters Garofalo, A. W., Wone, D. W., Phuc, A., Audia, J. E., Bales, C. A., Dovey, H. F., Dressen, D. B., Folmer, B., Goldbach, E. G., Guinn, A. C., Latimer, L. H., Mabry, T. E., Nissen, J. S., Pleiss, M. A., Sohn, S., Thorsett, E. D., Tung, J. S., Wu, J. 2002; 12 (21): 3051-3


    Potent, small molecule A beta inhibitors have been prepared that incorporate an alanine core bracketed by an N-terminal arylacetyl group and various C-terminal amino alcohols. The compounds exhibit stereospecific inhibition as demonstrated in an in vitro assay.

    View details for DOI 10.1016/s0960-894x(02)00684-4

    View details for PubMedID 12372499

  • Total Synthesis of Cacalol. The Journal of organic chemistry Garofalo, A. W., Litvak, J., Wang, L., Dubenko, L. G., Cooper, R., Bierer, D. E. 1999; 64 (9): 3369-3372

    View details for DOI 10.1021/jo9822838

    View details for PubMedID 11674448

  • Antihyperglycemic activities of cryptolepine analogues: An ethnobotanical lead structure isolated from Cryptolepis sanguinolenta JOURNAL OF MEDICINAL CHEMISTRY Bierer, D. E., Dubenko, L. G., Zhang, P. S., Lu, Q., Imbach, P. A., Garofalo, A. W., Phuan, P. W., Fort, D. M., Litvak, J., Gerber, R. E., Sloan, B., Luo, J., Cooper, R., Reaven, G. M. 1998; 41 (15): 2754-2764


    Cryptolepine (1) is a rare example of a natural product whose synthesis was reported prior to its isolation from nature. In the previous paper we reported the discovery of cryptolepine's antihyperglycemic properties. As part of a medicinal chemistry program designed to optimize natural product lead structures originating from our ethnobotanical and ethnomedical field research, a series of substituted and heterosubstituted cryptolepine analogues was synthesized. Antihyperglycemic activity was measured in vitro and in an NIDDM mouse model to generate the first structure-bioactivity study about the cryptolepine nucleus.

    View details for Web of Science ID 000074878000013

    View details for PubMedID 9667966

  • Synthesis of Chiral alpha,delta-Dioxygenated Allylic Stannanes as Reagents for Carbohydrate Synthesis and Homologation. The Journal of organic chemistry Marshall, J. A., Garofalo, A. W. 1996; 61 (25): 8732-8738


    The delta-oxygenated allylic stannanes 4.4 and 4.5, prepared through addition of Bu(3)SnLi to gamma-OTBS crotonaldehyde 4.3c followed by etherification of the adduct with TBS-Cl or MOM-Cl, undergo transmetalation with InCl(3) and in situ addition to aldehydes leading to mainly anti adducts 5.1 or 5.2, accompanied by varying amounts of syn diastereomers. Selectivities of >95:5 can be realized with the MOM reagent 4.5 and ynals 4.3d and 4.3e or cyclohexanecarboxaldehyde 4.3a. With enals 4.3b and 4.3c, 80:20 mixtures of anti and syn adducts are formed. The S enantiomer 10.1 of stannane 4.5 has also been prepared as a reagent for carbohydrate synthesis. Accordingly, addition to alpha-ODPS acetaldehyde 10.2 in the presence of InCl(3) leads to the adduct 10.3 as an inseparable 90:10 mixture of anti and syn diastereomers. Dihydroxylation of the OTBS derivative 10.4 affords the potential altrose precursor 10.5 in 81% yield.

    View details for DOI 10.1021/jo961671b

    View details for PubMedID 11667845