Our research group is primarily engaged in medicinal chemistry and organic synthetic chemistry. Currently, our laboratory is pursuing drug discovery research in areas that include 1) ophthalmic indications, 2) indications associated with elevated RBP4 expression, 3) TTR amyloidosis, 4) COVID-19, and 5) neuropathic pain. Training in our laboratory will involve organic synthesis and medicinal chemistry at its core, with significant exposure to pharmacology, ADME (Absorption, Distribution, Metabolism, and Excretion), and drug metabolism and pharmacokinetics.
Our lab contains state-of-the-art microwave synthesis technology, automated normal and reverse phase chromatography, and analytical HPLC and LCMS capability. We also have access to the Biomolecular NMR, Proteomics, and Analytical Biochemistry Core Facilities at RPI. Our projects utilize structural biology and computational chemistry to assist with drug design and we largely focus on preparing small molecule matrix libraries using state-of-the-art synthetic methods to elucidate structure-activity relationships (SAR) trends, modulate physicochemical properties, and optimize DMPK characteristics.
Synthetic Organic Chemistry
Pursuit of novel synthetic methodology development that may have broad utility within the organic synthetic and medicinal chemistry communities is also highly encouraged. Opportunities to explore and publish novel reactions is a component of the training provided within our laboratory.
Key Project Highlights:
Glycine Transporter 2 (GlyT2) Inhibitors – Neuropathic Pain:
We are engaged in an NIH-funded collaborative drug discovery project with the University of Sydney that focuses on developing novel and orally bioavailable GlyT2 inhibitors for the treatment of neuropathic pain. Approximately 116 million adults in the US suffer from chronic pain, which presents an incidence rate greater than that for sufferers of cancer, heart disease, and diabetes combined. Estimated associated US annual costs range from a staggering $560 to $635 billion and are projected to escalate. Despite the high level of prevalence and enormous socioeconomic burden incurred, pharmacological treatment of chronic pain remains limited as it is often refractory to currently available analgesics and many of these agents induce severe dose-limiting side effects or present a risk of tolerance, addiction, and abuse. The dearth of effective therapeutics for chronic pain has led to an overreliance on opioid medications, which are now the most commonly prescribed class of medications in the US and are fueling a national epidemic of overdose deaths and addictions. Thus, the discovery and development of new analgesics that are more effective and devoid of abuse and addiction liabilities remains a critical unmet need. Recent insights into the physiological adaptations underlying chronic pain have encouraged efforts to discover new classes of pain-relieving drugs that can selectively target these mechanisms. Among the myriad of cellular and molecular processes identified as contributing to pathological pain, disinhibition of spinal cord nociceptive signaling to higher cortical centers plays a critical role. Evidence suggests that impaired glycinergic neurotransmission develops in the dorsal horn of the spinal cord in neuropathic pain models and is an important CNS mechanism causing mechanical hyperalgesia (amplified pain signaling) and allodynia (a painful response to normally innocuous stimuli). Therefore, it has been hypothesized that agents capable of augmenting glycinergic tone within the dorsal horn may be able to obtund aberrant nociceptor signaling to the brain and serve as a novel class of analgesics. Indeed, drugs that enhance dysfunctional glycinergic transmission in neuropathic pain, and in particular inhibitors of GlyT2, are generating widespread interest. GlyT2 inhibitors have demonstrated broad analgesic efficacy in several preclinical models of varying pain modalities and could present a novel class of analgesics that are differentiated from current standard of care.
Bispecific Retinol Binding Protein 4 (RBP4) Antagonists/Transthyretin (TTR) Tetramer Kinetic Stabilizers – Atrophic Age-Related Macular Degeneration (AMD) and Stargardt Disease:
Accumulation of cytotoxic lipofuscin bisretinoids may contribute to atrophic age-related macular degeneration (AMD) pathogenesis, which is the most prevalent form of AMD. Retinal bisretinoid synthesis depends on the influx of serum all-trans-retinol delivered via a tertiary RBP4−TTR−retinol complex. We previously identified selective RBP4 antagonists, such as clinically investigated tinlarebant, that dissociate circulating RBP4−TTR−retinol complexes, reduce serum RBP4 levels, and inhibit bisretinoid synthesis in models of enhanced retinal lipofuscinogenesis. However, the release of TTR by selective RBP4 antagonists may be associated with TTR tetramer destabilization and, potentially, TTR amyloid formation. We are currently engaged in an NIH-funded drug discovery project in collaboration with Columbia University that focuses on the identification of bispecific RBP4 antagonist−TTR tetramer kinetic stabilizers, which may be especially important as a therapy for atrophic AMD patients who have another common age-related comorbidity, senile systemic amyloidosis (SSA), a nongenetic disease associated with wild-type TTR misfolding. These bispecific compounds also present potential therapeutic utility for treating Stargardt disease, an inherited form of macular degeneration.
Novel Antiviral Drugs – COVID-19:
We have entered into an NIH-funded collaborative drug discovery project with the Scripps Research Institute to identify novel antiviral drugs for treating COVID-19 (https://www.campp.org). This project is part of the multidisciplinary Center for Antiviral Medicines and Pandemic Preparedness (CAMPP), which was selected as one of the National Institute of Allergy and Infectious Diseases (NIAID) Antiviral Drug Discovery (AViDD) Centers for Pathogens of Pandemic Concern. The AViDD Centers' program is one of the U.S. government’s responses to the COVID-19 pandemic and is aimed at the near-term development of drugs against viruses with high pandemic potential — including coronaviruses, filoviruses (such as Ebola virus), flaviviruses (yellow fever virus, dengue virus, Zika virus), paramyxoviruses, bunyaviruses, and togaviruses.
B.S. Chemistry, 1994, Rensselaer Polytechnic Institute, Troy, NY 12180
Ph.D. Organic Chemistry, 2000, Rensselaer Polytechnic Institute, Troy, NY 12180
Medicinal Chemistry, Drug Discovery, Organic Chemistry
Organic Chemistry I (CHEM 2250)
Medicinal Chemistry (CHEM 4300/6300)
Wang, Y.; Ma, X., Muthuraman, P.; Raja, R.; Jayaraman, A.; Petrukhin, K.; Cioffi, C. L.; Ma, J-X.; Moiseyev, G. The novel visual cycle inhibitor (±)-RPE65-61 protects retinal photoreceptors from light-induced degeneration. PloS ONE 2022, PONE-D-21-38857 (Accepted, In Press).
Bafna, K. Cioffi, C.L.; Krug, R. M.; Montelione, G. T. Structural similarities between SARS-CoV2 3CLpro and other viral proteases suggest potential lead molecules for developing broad spectrum COVID-19 therapeutics", Front. Chem. Sec. Medicinal and Pharmaceutical Chemistry, 2022, doi: 10.3389/fchem.2022.948553.
Cioffi, C. L.; Raja, A.; Muthuraman, P.; Jayaraman, A.; Jayakumar, S.; Racz, B.; Varadi, A.; Petrukhin, K. Identification of transthyretin tetramer kinetic stabilizers that are capable of inhibiting the retinol-dependent retinol binding protein 4-transthyretin interaction: Potential novel therapeutics for macular degeneration, transthyretin amyloidosis, and their common age-related comorbidities. J. Med. Chem. 2021, 64, 9010-9041; PMID: 34138572.
Cioffi, C. L. Inhibition of glycine re-uptake: A potential approach for treating pain by augmenting glycine-mediated spinal neurotransmission and blunting central nociceptive signaling. Biomolecules 2021, 11, no. 6: 864.
Cioffi, C. L.; Muthuraman, P.; Raja, A.; Varadi, A.; Racz, B.; Petrukhin, K. Discovery of bispecific antagonists of retinol binding protein 4 that stabilize transthyretin tetramers: scaffolding hopping, optimization, and preclinical pharmacological evaluation as a potential therapy for two common age-related comorbidities. J. Med. Chem. 2020, 63, 11054-11084; PMID: 32878437;
Mostyn, S. N.; Sarker, S.; Muthuraman, P.; Raja, A.; Shimmon, S.; Rawling, T.; Cioffi, C. L.; Vandenberg, R. J. Photoswitchable ORG25543 congener enables optical control of glycine transporter 2. ACS Chem. Neurosci. 2020, 11, 1250-1258; PMID: 32191428.
Cioffi, C. L.; Racz, B.; Varadi, A.; Freeman, E.; Conlon, M.; Chen, P.; Zhu, L.; Kitchen, D.; Barnes, K.; Cywin, C.; Martin, W.; Pearson, P.; Johnson, G.; Blaner, W.; Petrukhin, K. Design, synthesis, and pre-clinical efficacy of novel nonretinoid antagonists of retinol binding protein 4 in the mouse model of hepatic steatosis. J. Med. Chem. 2019, 62, 5470-5500. PMID: 31079449.
Ma, Z.; King, K.; Alqahtani, M.; Worden, M.; Muthuraman, P.; Cioffi, C. L.; Shekhar Bakshi, C.; Malik, M. Stringent response governs the virulence and oxidative stress resistance of Francisella tularensis PloS ONE 2019, doi: https://doi.org/10.1101/653790.
Shin, Y., Moiseyev, G., Petrukhin, K., Cioffi, C. L., Muthuraman, P., Takahashi, Y., Ma, J. X. A novel RPE65 inhibitor CU239 suppresses visual cycle and prevents retinal degeneration. Biochim. Biophys. Acta. 2018, 1864, 2420-2429. PMID: 29684583.
Racz, B.; Varadi, A.; Kong, J.; Allikmets, R.; Pearson, P. G.; Johnson, G.; Cioffi, C. L.; Petrukhin, K. A non-retinoid antagonist of retinol-binding protein 4 rescues phenotype in a mouse model of Stargardt disease without inhibiting the visual cycle. J. Biol. Chem. 2018, 293, 11574-11588. PMID: 29871924.
Cioffi, C. L. Modulation of glycine-mediated spinal neurotransmission for the treatment of chronic pain. J. Med. Chem. 2018, 61, 2652-2679. PMID: 28876062.
Cioffi, C. L. Glycine transporter-1 inhibitors: a patent review (2011-2016). Expert Opin. Ther. Pat. 2018, 28, 197-210. PMID: 29338548.
Cioffi, C. L.; Liu, S.; Wolf, M.; Guzzo, P.; Sadalapure, K.; Parthasarathy, V.; Loong, D.; Maeng, J-H.; Carulli, E.; Fang, X.; Karunakaran, K.; Matta, L.; Choo, S. H.; Panduga, S.; Buckle, R.; Davis, R.; Sakwa, S.; Gupta, P.; Sargent, B.; Moore, N.; Luche, M.; Carr, G.; Khmelnitsky, Y.; Ismail, J.; Chung, M.; Bai, M.; Leong, W. Y.; Sachdev, N.; Swaminathan, S.; Mhyre, A. Synthesis and biological evaluation of N-((1-(4-(sulfonyl)piperazin-1-yl)cycloalkyl)methyl)benzamide inhibitors of glycine transporter-1. J. Med. Chem. 2016, 59, 8473-8494. PMID: 27559615.
Cioffi, C. L.; Guzzo, P, R. Inhibitors of glycine transporter-1: potential therapeutics for the treatment of CNS disorders. Curr. Top. Med. Chem. 2016, 16, 3404-3437. PMID: 27048272.
Cioffi, C. L.; Racz, B.; Freeman, E.; Conlon, M.; Chen, P.; Stafford, D.; Schwarz, D.; Zhu, L.; Kitchen, D.; Barnes, K.; Dobri, N.; Michelotti, E.; Cywin, C.; Martin, W.; Pearson, P.; Johnson, G.; Petrukhin, K. Bicyclic [3.3.0]-octahydrocyclopenta[c]pyrrolo antagonists of retinol binding protein 4: potential treatment of atrophic age-related macular degeneration and Stargardt disease. J. Med. Chem. 2015, 58, 5863-5888. PMID: 26181715.
Cioffi, C. L.; Dobri, N.; Freeman, E.; Conlon, M.; Chen, P.; Stafford, D.; Schwarz, D.; Golden, K.; Zhu, L.; Kitchen, D.; Barnes, K.; Racz, B.; Qin, Q.; Michelotti, E.; Cywin, C.; Martin, W.; Pearson, P.; Johnson, G.; Petrukhin, K. Design, synthesis, and evaluation of non-retinoid retinol binding protein 4 antagonists for the potential treatment of atrophic age-related macular degeneration and Stargardt disease. J. Med. Chem. 2014, 57, 7731-7757. PMID: 25210858.
Cioffi, C. L. Modulation of NMDA receptor funtion for the potential treatment of schizophrenia. Bioorg. Med. Chem. Lett. 2013, 23, 5034-5044. PMID: 23916256.
Cioffi, C. L.; Wolf, M. A.; Guzzo, P. R.; Sadalapure, K.; Parthasarathy, V.; Dethe, D.; Maeng, Jun-Ho; Carulli, E.; Loong, D. T. J.; Fang, X.; Hu, M.; Gupta, P.; Chung, M.; Bai, M.; Moore, N.; Luche, M.; Khmelnitsky, Y.; Love, P. L.; Watson, M. A.; Mhyre, A. J.; Liu, S.; Design, synthesis, and SAR of N-((1-(4-(propylsulfonyl)piperazin-1-yl)cycloalkyl)methyl)benzamide inhibitors of glycine transporter-1. Bioorg. Med. Chem. Lett. 2013, 23, 1257-1261. PMID: 23380375.
Manning, D.; Cioffi, C. L.; Usyatinsky, A.; Fitzpatrick, K.; Masih, L.; Guo, C.; Zhang, Z.; Sikkander, M-I.; Ryan, K.; Naginskaya, J.; Hassler, C.; Dobritsa, S.; Wierschke, J.; Early, W.; Butler, A.; Brady, C.; Barnes, N.; Cohen, M.; Guzzo, P. Novel serotonin type 3 receptor partial agonists for the potential treatment of irritable bowel syndrome. Bioorg. Med. Chem. Lett. 2011, 21, 58-61. PMID: 21146988.
Cioffi, C. L.; Lansing, J.; Yuksel, H., Synthesis of 2-aminobenzoxazoles from 2-aminophenols. featured article in SYNFACTS 2011, 2, 139; contributors: Victor Sniekus and Matthew O. Kitching.
Cioffi, C. L.; Lansing, J.; Yuksel, H. Synthesis of 2-aminobenzoxazoles using tetramethylorthocarbonate or 1, 1-dichlorodiphenoxymethane. J. Org. Chem. 2010, 75, 7942-7945. PMID: 20973518.
Yang, Z.; Fairfax, D. J.; Maeng, J.-H.; Masih, L.; Usyatinsky, A.; Hassler, C.; Isaacson, S.; Fitzpatrick, K.; DeOrazio, R. J.; Chen, J.; Harding, J. P.; Isherwood, M.; Dorbitsa, S.; Christensen, K. L.; Wierschke, J. D.; Bliss, B. I.; Peterson, L. H.; Beer, C. M.; Cioffi, C. L.; Lynch, M.; Rennels, W. M.; Richards, J. J.; Rust, T.; Khmelnitsky, Y. L.; Cohen, M. L.; Manning, D. D. Discovery of 2-substituted benzoxazole carboxamides as 5-HT3 receptor antagonists. Bioorg. Med. Chem. Lett. 2010, 20, 6538-6541. PMID: 20889341.
Cioffi, C. L.; Berlin, M.; Herr, R. J. Convenient palladium-catalyzed preparation of primary anilines using a fluorous benzophenone imine reagent. Synlett 2004, 841-845.
Cioffi, C. L.; Spencer, W.; Richards, J.; Herr, R. J. Generation of 3-pyridyl biaryl systems via palladium-catalyzed Suzuki cross-couplings of aryl halides with 3-pyridylboroxin. J. Org. Chem. 2004, 69, 2210-2212. PMID: 15058977.
Wentland, M.; Ye, Y.; Cioffi, C. L.; Lou, R.; Zhou, Q.; Xu. G.; Duan, W.; Denhardt, C.; Sun, X.; Cohen, D.; Bidlack, J. Synthesis and opioid receptor binding affinities of 8-amino-2, 6-methano-3-benzazocines. J. Med. Chem. 2003, 46, 838-849. PMID: 12593663.
Wentland, M.; Xu, G.; Cioffi, C. L.; Ye, Y.; Duan, W.; Cohen, D.; Colasurdo, A.; Bidlack, J. 8-aminocyclazocine analogues: synthesis and structure-activity relationships. Bioorg. Med. Chem. Lett. 2000, 10, 183-187. PMID: 10673107.
Hough, L.; Nalwalk, B.; Leurs, W.; Menge, H.; Timmerman, M.; Cioffi, C. L.; Wentland, M. Novel qualitative structure-activity relationships for the antinociceptive actions of H2 antagonists, H3 antagonists and derivatives. J. Pharmacol. Exper. Ther. 1997, 283, 1534-1543. PMID: 9400031.
Frye, L.; Pechulis, A.; Bellevue, F.; Cioffi, C. L.; Trapp, S.; Fojitik, J.; McKitty, A.; Kinney, W. Synthesis of 24(epi)-squalamine, an anti-infective steroidal polyamine. J. Org. Chem. 1995, 60, 5121-5126.