Delving into the Latest Updates on Pyrimethamine with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

2,4-Diamino-5-(4-chlorophenyl)-6-ethylpyrimidine, 2,4-Diamino-5-(P-chlorophenyl)-6-ethylpyrimidine, 2,4-Diamino-5-chlorophenyl-6-ethylpyrimidine

+ [18]

Target

DHFR

Mechanism

DHFR inhibitors(Dihydrofolate reductase inhibitors)

Therapeutic Areas

Infectious DiseasesNeoplasms

Active Indication

Infectious DiseasesAcute MalariaMalaria+ [2]

Inactive Indication-

Originator Organization

Vyera Pharmaceuticals LLC

Active Organization

TILDE SCIENCES LLC

Arrotex Pharmaceuticals Pty Ltd.Startup

Inactive Organization-

Drug Highest PhaseApproved

First Approval Date

US (23 Jan 1953),

Acute MalariaMalariaToxoplasmosis

RegulationOrphan Drug (US)

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Structure

Molecular FormulaC12H13ClN4

InChIKeyWKSAUQYGYAYLPV-UHFFFAOYSA-N

CAS Registry58-14-0

The ORBIT trial is part of a worldwide search for a functional cure of HIV. One such cure strategy aims to reverse HIV in the reservoir from latency by increasing cell-associated HIV-RNA, which will lead to increased antigen presentation, trigger immune recognition, and facilitate the elimination of reservoir cells (so-called 'shock and kill' approach to HIV cure). Participants of the trial are adults with HIV with undetectable viral load that are able to give informed consent to participate in the trial, in total 49 patients will be recruited. The investigational medical compounds in this trial are panobinostat, lenalidomide and pyrimethamine. These are all licensed drugs for other conditions. Participants of this trial will receive a single dose of the IMPs, either as monotherapy or as combination therapy. Sampling will be performed before, during and after medical treatment to evaluate latency reversal, reservoir reduction and safety endpoints. Patients will be recruited from the Erasmus MC, Amsterdam university Medical Center and the University Medical Center Utrecht.

Start Date01 Apr 2024

Sponsor / Collaborator

Erasmus MC

NCT05678348 / RecruitingEarly Phase 1IIT

Early Phase I Window of Opportunity Biomarker and Safety Trial to Test Pyrimethamine as an Inhibitor of NRF2 in HPV-unrelated, Locally Advanced Head and Neck Squamous Cell Carcinoma

NRF2 activation, observed in up to 40% of head and neck squamous cell carcinoma (HNSCC) tumors, plays a critical role in tumor progression, metastasis, and radiation therapy resistance. The investigators have recently discovered that pyrimethamine (PYR) and its analogs have an inhibitory effect on NRF2 activity in vitro and in mouse models via inhibition of dihydrofolate reductase (DHFR).
Pyrimethamine is an established drug that has been used for decades for treatment of protozoan infections and malaria. A growing body of research shows that it has potential antitumor activity, however its activity on growing human tumors has not been previously studied. The primary efficacy goal of this study is to evaluate the activity of pyrimethamine on human tumors as demonstrated by inhibition of DHFR and downregulation of NRF2 pathway activity. On-target inhibition of DHFR by pyrimethamine results in the stabilization and increased protein expression of human DHFR.
The primary efficacy hypothesis of this study is that treatment with pyrimethamine will result in a 50% increase in DHFR protein within the tumor cells as measured by quantitative western blot analysis. Secondarily, among those tumors classified as NRF2-active on pre-treatment biopsy, the investigators hypothesize there will be a 50% reduction in NRF2 activity as measured by SureQuant targeted proteomic analysis.

Start Date03 Aug 2023

Sponsor / Collaborator

Washington University School of Medicine

[+1]

JPRN-jRCTs071180092 / RecruitingPhase 2/3IIT

Efficacy and safety of pyrimethamine/sulfadiazine/folinate combination therapy for the treatment of ocular toxoplasmosis - Treatment of ocular toxoplasmosis with pyrimethamine/sulfadiazine

Start Date14 Apr 2020

Sponsor / Collaborator-

100 Clinical Results associated with Pyrimethamine

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100 Translational Medicine associated with Pyrimethamine

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100 Patents (Medical) associated with Pyrimethamine

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9,032

Literatures (Medical) associated with Pyrimethamine

31 Dec 2024·Renal failure

Comparison of citrate dialysate in pre- and post-dilution online hemodiafiltration: effect on clot formation and adequacy of dialysis in hemodialysis patients

Article

Author: Homjan, Monpinya Charttong ; Laykhram, Thanachit ; Trakarnvanich, Thananda ; Jitraree, Arisara ; Nakornchai, Pasu

BACKGROUND:

Citrate dialysate (CD) has been successfully used in conventional hemodialysis and continuous renal replacement therapy; however, no study has compared pre- and post-dilution online hemodiafiltration (oL-HDF). Therefore, we aimed to investigate the efficacy of citrate anticoagulation for oL-HDF and the metabolic changes and quality of life of patients on hemodialysis treated using both modes.

METHOD:

Eight dialysis patients were treated with CD containing 0.8 mmol of citric acid for 4 weeks in each phase. Visual clotting scores were investigated as the primary endpoints. Adequacy of dialysis, laboratory parameters, and quality of life were measured as secondary objectives.

RESULTS:

The mean clotting scores in the pre-dilution mode were significantly lower than those in the post-dilution mode and in all phases except the heparin-free phase (p < 0.001 in the baseline phase, p = 0.001 in phase 1, and p = 0.023 in phase 2). The values of Kt/V in both modalities were comparable except during the baseline phase, in which the values of pre-dilution were significantly greater than post-dilution (2.36 ± 0.52/week vs. 1.87 ± 0.33/week;95% CI -0.81 to -0.19, p = 0.002). The patient's quality of life regarding their physical activity level was significantly higher in the post-dilution mode than in the pre-dilution mode at baseline and in phase 1 (p = 0.014 and 0.004 at baseline and in phase 1, respectively). Metabolic changes did not differ between the two modes.

CONCLUSION:

Citrate dialysate decreased or prevented anticoagulation in both pre- and post-dilution modes of oL-HDF without significant side effects and had comparable adequacy of dialysis.

12 Dec 2024·JOURNAL OF MEDICINAL CHEMISTRY

Development of Potent and Selective Inhibitors of Methylenetetrahydrofolate Dehydrogenase 2 for Targeting Acute Myeloid Leukemia: SAR, Structural Insights, and Biological Characterization

Article

Author: Wu, Su-Ying ; Hsu, Tsu ; Peng, Yi-Hui ; Wang, Yi-Hsin ; Jiaang, Weir-Torn ; Kuo, Ching-Chuan ; Lu, Cheng-Tai ; Yeh, Teng-Kuang ; Tang, Ya-Chu ; Chang, Hsin-Huei ; Hsueh, Ching-Cheng ; Huang, Chih-Hsiang ; Lin, Li-Mei ; Hsieh, Chih-Chien ; Kung, Fang-Chun ; Huang, Yu-Chen ; Huang, Zih-Ting ; Lee, Lung-Chun ; Chang, Ling ; Li, Li-Hsuan

Methylenetetrahydrofolate dehydrogenase/cyclohydrolase 2 (MTHFD2), a pivotal mitochondrial enzyme in one-carbon metabolism, is significantly upregulated in various cancers but minimally expressed in normal proliferating cells. In contrast, MTHFD1, which performs similar functions, is predominantly expressed in normal cells. Therefore, targeting MTHFD2 with selective inhibitors holds promise for a broader therapeutic window with reduced toxicity and fewer side effects. This study identified selective 2,4-diamino-6-oxo-1,6-dihydropyrimidin-5-yl ureido-based derivatives through systematic chemical modifications and SAR studies. Structural biology investigations revealed substitutions in the phenyl ring and tail region modulate potency and selectivity toward MTHFD2. Additionally, a comprehensive cell screening platform revealed acute myeloid leukemia cells with FLT3 internal tandem duplication mutations are particularly sensitive to these inhibitors. Furthermore, synergistic effects were observed when combining potential compounds with Alimta. Compound 16e emerged as a leading candidate, demonstrating superior inhibition and selectivity for MTHFD2, favorable pharmacokinetics, and potent antitumor efficacy in MOLM-14 xenograft models.

01 Dec 2024·International Journal for Parasitology-Drugs and Drug Resistance

Profile of molecular markers of Sulfadoxine-Pyrimethamine-resistant Plasmodium falciparum in individuals living in southern area of Brazzaville, Republic of Congo

Article

Author: Djontu, Jean Claude ; Mouanga, Alain Maxime ; Umuhoza, Dieu Merci ; Ntoumi, Francine ; NTOUMI, Francine ; Lissom, Abel ; NGUIMBI, Etienne ; BOUMPOUTOU, Reauchelvy Kamal ; Mbama Ntabi, Jacque Dollon ; ASSIORO DOULAMO, Naura veil ; VOUVOUNGUI, Christevy Jeanney ; Assioro Doulamo, Naura veil ; Nguimbi, Etienne ; LISSOM, Abel ; MBAMA NTABI, Jacque Dollon ; MOUANGA, Alain Maxime ; Boumpoutou, Reauchelvy Kamal ; Assioro Doulamo, Naura Veil ; Vouvoungui, Christevy Jeanney ; UMUHOZA, Dieu Merci ; BAINA, Marcel Tapsou ; Baina, Marcel Tapsou ; DJONTU, Jean Claude

BACKGROUND:

Although the seasonal and perennial malaria chemopreventions are not implemented in the Republic of Congo, resistance to Sulfadoxine-pyrimethamine (SP) threatens the intermittent preventive treatment during pregnancy (IPTp-SP) and others treatments using the drug. The objective of this study was to determine the prevalence of molecular markers of P.falciparum resistance to SP in individuals with microscopic malaria infection in the south of Brazzaville.

METHODS:

Two parallel surveys (health facilities and community-based cross sectional studies) were carried out in urban and rural areas in southern Brazzaville. Between March and October 2021, blood samples were collected from 328 P. falciparum microscopic positive individuals (1-83 years old, and sex ratio female/male of 1.1) to characterize dhfr and dhps genes involved in the P.falciparum resistance to SP. Restriction Fragment Length Polymorphism PCR was used for the detection of mutations within these parasite genes.

RESULTS:

High prevalence of mutations was reported within Pfdhfr gene: N51I; 328/328 (100%) ratio (prevalence) [95 CI uncertainty], C59R; 317/328 (96.6 %) [94.1-98.1%], S108N; 326/326 (100%), N164L; 3/326 (0.9%) [0.3-2.7%], and Pfdhps gene: A437G; 292/327 (89.3%) [85.5-92.2%], K540E; 140/327(42.8 %) [37.6-48.2%], A581G; 136/325 (41.8%) [36.6-42.3%]. The quintuple mutant (N51I + C59R + S108N + A437G + K540E) and sextuple mutant haplotypes (N51I + C59R + S108N + A437G + K540E + A581G) were reported for 11/144 (7.6%) [4.3-13.2%] and 5/144 (3.4%) [1.5-7.9%]) of the participants respectively. The K540E and A437G mutants were more prevalent in the rural community; 81/139 (58.3%) [50.0-66.1%] and 135/139 (97.1%) [92.8-98.9%] respectively) than in the urban community; 21/50 (46.3%) [33.7-59.4%] and 47/54(87.0%) [75.6-93.6%] (p = 0.004 and p˂0.0001 respectively) CONCLUSION: These results indicate high prevalence of SP resistance mutations within the dhfr and dhps genes of P. falciparum isolates circulating in study sites, which may limit the efficacy of treatments using SP in these settings.

24

News (Medical) associated with Pyrimethamine

07 Oct 2024

·endpts.com

Supreme Court declines to review patent battle over inhalation powder Yutrepia

Liquidia’s stock $LQDA rose about 10% on Monday following a win in the US Supreme Court for its treprostinil inhalation powder Yutrepia. Liquidia has been fighting United Therapeutics over competing drugs in various court battles over the last several years. The FDA handed down a tentative approval for Yutrepia in August, but also said that Yutrepia won’t receive final approval until Tyvaso’s regulatory exclusivity is over in May 2025. Liquidia’s drug is approved to treat adults with pulmonary arterial hypertension (PAH) and pulmonary hypertension associated with interstitial lung disease (PH-ILD). “United Therapeutics has pulled out all the stops to prevent our product from coming to market at all. And I think with this decision, this product is now going to come to market,” Liquidia’s chief business officer Jason Adair told Endpoints News . “I think that’s a big milestone for us as a company, is that this product is going to come to market when the regulatory exclusivity expires, if not earlier.” In an announcement , Liquidia said the court rejected United Therapeutics’ petition which requested permission to appeal prior decisions in Liquidia’s favor that found that all claims of one of United’s patents are unpatentable. The company added in its announcement that there are currently no patents preventing final FDA approval of Yutrepia, although a trial over another patent is scheduled for June 2025. Thanks to the Supreme Court, the 2022 decision by the Patent Trial and Appeal Board, which invalidated United’s claims of patent infringement — and a decision by the US Court of Appeals for the Federal Circuit in 2023 that upheld the board’s decision — are now final and can’t be appealed. Jeffs wrote in a statement that that patent is now unenforceable and Liquidia will “fight for the earliest possible launch” of Yutrepia. Also on Monday, SCOTUS declined to hear a case involving former pharma executive Martin Shkreli, as he sought to reverse a $65 million payment he owes following allegations around his raising the price of the HIV drug Daraprim. Editor’s note: This story has been updated to correctly identify Jason Adair’s quote.

Drug ApprovalPatent InfringementPatent Expiration

12 Dec 2023

·www.businesswire.com

AscellaHealth and Tilde Sciences Team Up to Launch Best-in-Class Patient-Centric Program for Increased Access to Daraprim® and Enhanced Patient Outcomes

BERWYN, Pa.--( BUSINESS WIRE )-- AscellaHealth , a global healthcare and specialty pharmacy (SP) solutions company, announces that Tilde Sciences , specializing in the development and commercialization of specialty pharmaceuticals, has chosen AscellaHealth’s Specialty Pharmacy, Optime Care as its exclusive distribution, specialty pharmacy and hub/patient services partner. This selection is based upon their impressive track-record for seamlessly launching branded pharmaceutical programs for specialty and rare disease pharma/biotech manufacturers and their exceptional personalized patient care services and resources to support Daraprim®. Through the partnership, patients will experience uninterrupted access to this medication, with distinctive, tailored support programs implemented by expert care coordinators and innovative technology platforms to support custom patient communications, including educational support and interventions at key points in therapy that result in optimal compliance. Dea Belazi, president and CEO, AscellaHealth, says, “Tilde Sciences recognizes the value of our years of experience in understanding the unique needs of patients with rare and orphan diseases or complex chronic conditions, expertise that clearly differentiates our patient-centric, end-to-end solutions and offers a more ‘human touch’ for people facing chronic illness and uncertainty. Designed to address the unmet needs of clients and patients, our capabilities encompass all milestones throughout the product lifecycle and beyond, with an exemplary level of personalized care management customized for specific therapies and proven to result in better individual outcomes and outstanding compliance rates. Proprietary technology and patient engagement tools provide actionable data metrics for program optimization every step of the way.” This revolutionary patient support program goes well beyond a typical information hotline or static web information. Patients are the central point of focus for all services and programs which include individual care plans that address the ongoing care issues for patients, caregivers and families. Outreach is conducted during key points in therapy and technology tools support phone, email, text and mobile apps to effectively streamline communication and increase response rates. Throughout all stages of the patient journey, spanning program enrollment, welcome/benefits verification, prior authorization and financial assistance, care coordination, fulfillment and patient compliance, the personalized care of trained and skilled patient care coordinators is a hallmark of this approach. Akeel Mithani, CEO of Tilde adds, “access to medications in the US has become increasingly complex. This poses a particular challenge for patients suffering from rare and serious diseases. Time is of the essence in getting patients the medications they need to be well. At Tilde Sciences, our mission is to be on the forefront of identifying solutions that simplify access for critically ill patients. Our core belief is that people make the difference. We have selected AscellaHealth’s Specialty Pharmacy, Optime Care as our partner to service patients in need of our medicines. This was a decision we did not take lightly. Ultimately, we are confident that the people at AscellaHealth and Optime Care share our genuine care and concern for rare disease patients. We are thrilled to work together to simplify access to Daraprim®.” About AscellaHealth LLC AscellaHealth, a global healthcare and specialty pharmacy solutions organization, serving patients, life sciences manufacturers, payers and providers, offers a comprehensive portfolio of uniquely tailored, tech-enabled services supporting complex, chronic conditions or rare diseases that require specialty medications and/or cell and gene therapies. A recipient of numerous industry awards for innovation, including Deloitte Technology Fast 500™ and Inc. 5000, AscellaHealth’s customized, patient-centric approach is built upon proprietary technology processes for end-to-end solutions to streamline the commercialization of specialty medications and proactively address unmet client needs, optimize clinical health outcomes and improve the quality of life for this patient population. AscellaHealth brings a rare and special perspective to all stakeholders. Visit www.AscellaHealth.com . About Tilde Tilde Sciences is a United States based biopharmaceutical company specializing in the development and commercialization of specialty pharmaceuticals tailored for rare diseases with significant unmet needs. For more information visit https://www.tildesciences.com/ .

12 Dec 2023

·www.businesswire.com

AscellaHealth and Tilde Sciences Team Up to Launch Best-in-Class Patient-Centric Program for Increased Access to Daraprim® and Enhanced Patient Outcomes

BERWYN, Pa.--( BUSINESS WIRE )-- AscellaHealth , a global healthcare and specialty pharmacy (SP) solutions company, announces that Tilde Sciences , specializing in the development and commercialization of specialty pharmaceuticals, has chosen AscellaHealth’s Specialty Pharmacy, Optime Care as its exclusive distribution, specialty pharmacy and hub/patient services partner. This selection is based upon their impressive track-record for seamlessly launching branded pharmaceutical programs for specialty and rare disease pharma/biotech manufacturers and their exceptional personalized patient care services and resources to support Daraprim®. Through the partnership, patients will experience uninterrupted access to this medication, with distinctive, tailored support programs implemented by expert care coordinators and innovative technology platforms to support custom patient communications, including educational support and interventions at key points in therapy that result in optimal compliance. Dea Belazi, president and CEO, AscellaHealth, says, “Tilde Sciences recognizes the value of our years of experience in understanding the unique needs of patients with rare and orphan diseases or complex chronic conditions, expertise that clearly differentiates our patient-centric, end-to-end solutions and offers a more ‘human touch’ for people facing chronic illness and uncertainty. Designed to address the unmet needs of clients and patients, our capabilities encompass all milestones throughout the product lifecycle and beyond, with an exemplary level of personalized care management customized for specific therapies and proven to result in better individual outcomes and outstanding compliance rates. Proprietary technology and patient engagement tools provide actionable data metrics for program optimization every step of the way.” This revolutionary patient support program goes well beyond a typical information hotline or static web information. Patients are the central point of focus for all services and programs which include individual care plans that address the ongoing care issues for patients, caregivers and families. Outreach is conducted during key points in therapy and technology tools support phone, email, text and mobile apps to effectively streamline communication and increase response rates. Throughout all stages of the patient journey, spanning program enrollment, welcome/benefits verification, prior authorization and financial assistance, care coordination, fulfillment and patient compliance, the personalized care of trained and skilled patient care coordinators is a hallmark of this approach. Akeel Mithani, CEO of Tilde adds, “access to medications in the US has become increasingly complex. This poses a particular challenge for patients suffering from rare and serious diseases. Time is of the essence in getting patients the medications they need to be well. At Tilde Sciences, our mission is to be on the forefront of identifying solutions that simplify access for critically ill patients. Our core belief is that people make the difference. We have selected AscellaHealth’s Specialty Pharmacy, Optime Care as our partner to service patients in need of our medicines. This was a decision we did not take lightly. Ultimately, we are confident that the people at AscellaHealth and Optime Care share our genuine care and concern for rare disease patients. We are thrilled to work together to simplify access to Daraprim®.” About AscellaHealth LLC AscellaHealth, a global healthcare and specialty pharmacy solutions organization, serving patients, life sciences manufacturers, payers and providers, offers a comprehensive portfolio of uniquely tailored, tech-enabled services supporting complex, chronic conditions or rare diseases that require specialty medications and/or cell and gene therapies. A recipient of numerous industry awards for innovation, including Deloitte Technology Fast 500™ and Inc. 5000, AscellaHealth’s customized, patient-centric approach is built upon proprietary technology processes for end-to-end solutions to streamline the commercialization of specialty medications and proactively address unmet client needs, optimize clinical health outcomes and improve the quality of life for this patient population. AscellaHealth brings a rare and special perspective to all stakeholders. Visit www.AscellaHealth.com . About Tilde Tilde Sciences is a United States based biopharmaceutical company specializing in the development and commercialization of specialty pharmaceuticals tailored for rare diseases with significant unmet needs. For more information visit https://www.tildesciences.com/ .

100 Deals associated with Pyrimethamine

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External Link

KEGG	Wiki	ATC	Drug Bank
D00488	Pyrimethamine	P01BD01	DB00205

R&D Status

Approved

10 top approved records.

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Indication	Country/Location	Organization	Date
Infectious Diseases	AU	Arrotex Pharmaceuticals Pty Ltd.Startup	11 Nov 2003
Acute Malaria	US	TILDE SCIENCES LLC	23 Jan 1953
Malaria	US	TILDE SCIENCES LLC	23 Jan 1953
Toxoplasmosis	US	TILDE SCIENCES LLC	23 Jan 1953

Developing

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Locally Advanced Head and Neck Squamous Cell Carcinoma	Phase 1	US	TILDE SCIENCES LLC	03 Aug 2023

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


SSIEM2022	Not Applicable	homozygous p.L483P mutation	-	Phenylbutyrate	atfowthizu(kpvtorjcck) = jmamaqgwlk xkpycfhofh (syhjzxcqxb )	-	30 Aug 2022
				Ursodeoxycholic acid	atfowthizu(kpvtorjcck) = yrjmmfpezf xkpycfhofh (syhjzxcqxb )
NCT03952650 (CTgov)	Phase 1/2	Malaria	252	PYR+PfSPZ (1a - Pilot/Safety: Dosing Interval on Days: 1)	kybawjnwnn(nrzpgxjsug) = ehcsjpzsvk pwkzalodjv (xgwhazedrr, zzjbppranf - ffboxmfjdb) View more	-	12 Jul 2022
				PYR+PfSPZ (2a - Pilot/Safety: Dosing Interval on Days: 1)	kybawjnwnn(nrzpgxjsug) = caccobeyyb pwkzalodjv (xgwhazedrr, ffdohepcto - firkofadqs) View more
LRAs United as a Novel Anti-HIV strategy (IAS2022)	Not Applicable	HIV Infections	-	Pyrimethamine	jswkbtyupz(gihtwxfzbg) = mctzosasqu lzspavxswv (hzxitepmwn )	-	01 Jan 2022
NCT03258762 (CTgov)	Phase 1	Toxoplasmosis	14	calcium folinate+Pyrimethamine (Healthy Japanese Participants)	wuxcjejiqh(vjmmdxbbal) = fvtexxmbkw prollsazgv (secidxhthh, awnbzhdytn - epjogktfwe) View more	-	27 Mar 2019
				calcium folinate+Pyrimethamine (Healthy Caucasian Participants)	vtwhsmfewi(mcknjchtfn) = erwnwwcfqp lwkuxdghdj (qoigtdokgu, iaepfrkkwy - xmggepznff) View more
NCT01083667 (CTgov)	Phase 1/2	Amyotrophic Lateral Sclerosis	32	Pyrimethamine	arnbjzppuf(xqfarbkiwa) = thocqmwntn kfcfrawsrv (bmwsqwzbdv, zggannwues - vgiclciiag) View more	-	19 Jun 2017