PF-07817883 (ibuzatrelvir) is an oral, second-generation SARS-CoV-2 M^pro inhibitor developed by Pfizer. These efforts follow the success of Pfizer's antiviral combination drug, Paxlovid, which was granted Emergency Use Authorization by the FDA for the treatment of COVID-19. PF-07817883 was granted Fast Track designation and recently completed a Ph. II clinical trial in outpatient adults with COVID-19 symptoms. This article details the discovery strategy for PF-07817883, which includes addressing metabolic soft spots identified through MetID studies, recent clinical developments, and more.

AM-2-19 (SF001) is an analog of the notoriously toxic IV antifungal drug, amphotericin B (AmB). Compared with AmB, AM-2-19 is significantly less toxic against primary human cells and in mice, while more broadly active against fungal pathogens including antifungal drug-resistant strains. SF001 received Fast-Track Designation from the FDA in 2023 and has progressed to Ph. I clinical development. This article highlights the history of antifungal polyene natural products, a new mechanistic hypothesis for polyene antibiotic activity, and the design of 3rd generation Erg-specific polyenes.

Recently, Novartis disclosed a new class of brain-penetrant, covalent agents against kinetoplastid parasites in Science. Kinetoplastid parasites cause Chagas disease (T. cruzi), sleeping sickness (T. brucei), and leishmaniasis (Leishmania), but there are few effective treatment options, especially for infections in the brain (e.g. stage II sleeping sickness).

The orally administered gepotidacin is a member of a novel class of type IIA topoisomerase inhibitors , also called novel bacterial topoisomerase inhibitors ( NBTIs ), for which the mode of action and binding mode with a topoisomerase was first disclosed in 2010 by [...]

GS-6207 is an HIV-1 inhibitor that acts on the capsid protein monomer (p24), which normally self-assembles in the HIV virion to form the capsid core that is essential for virus infectivity. GS-6207 targets a protein-protein interaction between the small (24 kDa) p24 monomers, binding in a glue-like fashion to two separate monomers, and is [...]

A Ph. II liver-targeting HBV core protein modulator optimized for ADMET properties. Linvencorvir (RG7907), a novel HBV core protein allosteric modulator, offers a promising treatment option for chronic hepatitis B which affects 296 million people globally. It possesses an interesting glue-like mechanism that causes the HBV core protein to [...]

Recently disclosed in Nature , Janssen’s JNJ-1802 is the first dengue virus NS3-NS4B protein-protein interaction inhibitor to enter the clinic. The molecule is derived from a related chemical series to JNJ-A07 , which was also disclosed in Nature in 2021 and highlighted as a Molecule of [...]

Overview. A common route of resistance to tuberculosis involves Mtb erm37 expression, which expresses an RNA methyltransferase that methylates the A2058 position of the 23S ribosome RNA , hindering macrolide antibiotic binding. The sequanamycins (SEQs) are a class of molecules that overcomes this resistance mechanism, primarily attributed to [...]

Harnessing a novel mechanism for HIV eradication with a new class of bifunctional molecules. Modern antiretroviral therapies (ARTs) efficiently block HIV-1 replication, but are not completely curative because they can’t deplete viral reservoirs hidden from the immune system within the host genome . PYR01 is an HIV antiviral which, unlike [...]

Newly disclosed HIV-1 antiretroviral is the first integrase-LEDGF/p75 allosteric HIV-1 inhibitor to clear Ph. I safety trials. Biodim has recently disclosed a small molecule candidate, BDM-2 , that demonstrates nanomolar activity against HIV-1 replication in vitro and showed promising safety in healthy subjects in a 2020 Ph. I clinical trial [...]

Our latest roundup of small molecules in the news includes two potential upcoming approvals: rezafungin Rezafungin (CD-101) is a once-weekly IV antifungal agent and next-generation echinocandin (glucan synthase inhibitor) that demonstrated non-inferiority vs. standard of care caspofungin (IV QD) (NCT03667690). An FDA AdCom voted 14 to 1 in [...]

SPR720 (pVXc-486) is an oral prodrug of a dual inhibitor of the bacterial DNA gyrase and topoisomerase IV ATPase catalytic domains, GyrB and ParE . The molecule was in-licensed by Spero Therapeutics , a 2014 “Fierce 15” startup , from Vertex ( WO2014014845A1 , US20140031318 ), and is now Spero’s lead development program after [...]

Context. AN15368 (Anacor Pharmaceuticals) is an oral Cleavage And Polyadenylation Specificity Factor (CPSF3) inhibitor being developed for Chagas disease, also known as American trypanosomiasis. Chagas disease is caused by Trypanosoma cruzi and is estimated to affect 6-7 million people worldwide, primarily those living in Latin America. The [...]

Context. UCB7362 (UCB Biopharma) is an oral plasmepsin X (PMX) inhibitor being developed as an antimalarial agent. Malaria is a protozoan disease caused by Plasmodium sp. and remains a significant public health concern in many parts of the world, with 627,000 reported global deaths in 2020 despite the significant strides in the antimalarial [...]

Context. ICeD-2 (Merck) is a dipeptidyl peptidase 9 (DPP9) inhibitor under development for HIV-1 infections. Despite the significant advancements in antiretroviral therapy research leading to the approval of some highly effective treatments , the cure for HIV-1 infection has been elusive. A phenotypic screen looking at compound-induced HIV-1 [...]

Context. GST-HG131 (WuXi AppTec) is an oral hepatitis B virus (HBV) inhibitor which lowers hepatitis B antigen (HBsAg) levels which entered clinical development in Chinese subjects for chronic hepatitis B infection. Despite the significant research strides made in the elucidation of the biology of HBV, chronic HBV infection continues to [...]

Context. “ Compound 7 ” (NIBR) is an oral Trypanosoma brucei 20S proteasome inhibitor being developed for Human African Trypanosomiasis (HAT). African sleeping sickness , or HAT, is caused by a parasite in the genus Trypanosoma .  The parasite is spread by the Tsetse fly, and the lifecycle of the parasite involves a phase in the blood of the [...]

In August 2022, the European Medicines Agency granted Marketing Authorization to lenacapavir (Sunlenca), the first-in-class bi-annually dosed HIV capsid inhibitor indicated for multidrug-resistant HIV-1 infection. This Premium deep dive into Sunlenca includes: the industry context the clinical data the target rationale the mechanism of action [...]

Context. TXA6101 (TAXIS Pharmaceuticals) is a filamentous temperature-sensitive mutant Z (FtsZ) protein inhibitor being developed for targeting gram-negative bacteria. Drug resistance continues to be a paramount challenge in antibiotic therapy and there is an ongoing need to explore and develop novel antibacterial drugs. FtsZ has long been [...]

There were two novel small molecules approved in May 2022: vonoprazan (Voquezna) : a potassium-competitive acid blocker (PCAB) tapinarof (Vtama) : an aryl hydrocarbon receptor (AhR) agonist And one novel large molecule approval: tirzepatide (Mounjaro) : a glucose-dependent insulinotropic polypeptide (GIP) receptor and glucagon-like peptide-1 [...]

The FDA in 2021 approved four novel small molecule drugs for various infectious diseases, including human immunodeficiency virus type-1 (HIV-1), post-transplant cytomegalovirus (CMV), vulvovaginal candidiasis, and human African trypanosomiasis (HAT; sleeping sickness). This article and slide deck explores each in more detail, including but [...]

Context. “Compound 14” (Shionogi) is an HIV-1 protease inhibitor being developed for HIV treatment . Despite the existence of two generations and a total of nine approved agents targeting the well-validated HIV-1 protease, issues with drug resistance and toxicity still persist, highlighting the need for novel agents with unique mechanisms of [...]

In this highlight, Dr. Dennis C. Koester reviews treatment options for HIV and explains how small molecule long-acting injectables (LAIs) are offering significant promise in both HIV treatment and prophylaxis. A Coming Paradigm Shift for HIV Treatment and Prophylaxis By Dennis C. Koester The surge of the coronavirus pandemic has made our [...]

There were two novel small molecules approved in April 2022: mavacamten (Camzyos), an oral cardiac myosin inhibitor oteseconazole (Vivjoy), an oral antifungal ( jump to section ) This deep dive explores each drug in more detail, including the industry context, the clinical data, the target rationale, mechanisms of action, and drug origins [...]

INE963 (Novartis Institute for Tropical Diseases) is an oral, single dose, fast-acting blood-stage antimalarial candidate . The molecule was identified using a phenotypic high-throughput screening approach which has been successfully used to identify new antimalarial chemotypes . Phenotypic screens can be preferable to target-based [...]

It’s always nice to see a small molecule making the front page of the news , especially when it’s a Molecule of the Month from last year! Pfizer and ReViral announced an agreement for Pfizer to acquire ReViral for up to $525 million, including milestones (amount upfront not disclosed). ReViral’s lead molecule sisunatovir, is an oral [...]

We asked the global drug discovery community to nominate and vote on their favorite molecule from 2021, and the results are in. The 2021 choice for Drug Hunter’s Small Molecule of the Year is Pfizer’s CoV-2 M pro Inhibitor, PF-07321332 (nirmatrelvir, Paxlovid) . Published in a November 2021 Science article , the molecule was praised for its [...]

GSK3640254, one of January 2022's Molecules of the Month , is an HIV maturation inhibitor and Ph. IIb clinical candidate (60-180 mg PO QD) with activity against a range of HIV strains with Gag polymorphisms. The first HIV maturation inhibitor to read out clinically was bevirimat (Myriad Genetics), derived from a natural product first [...]

S-217622 is the first oral, non-covalent, non-peptidic SARS-CoV-2 3CL (main protease) inhibitor clinical candidate, currently in Ph. II/III trials as a once-daily oral treatment for COVID-19. Unlike paxlovid , the molecule is a non-covalent inhibitor, which may lead to a better safety profile in large populations, though there is no reason to [...]

GSK3640254 is an HIV maturation inhibitor and Ph. IIb clinical candidate (60-180 mg PO QD) with activity against a range of HIV strains with Gag polymorphisms. The first HIV maturation inhibitor to read out clinically was bevirimat (Myriad Genetics), derived from a natural product first isolated from a Chinese herb. Maturation inhibitors like [...]

Pfizer’s PF-07321332 (API of Paxlovid) is an oral, reversible covalent SARS-CoV-2 main protease inhibitor, which received emergency use authorization from the FDA for Covid treatment at the end of 2021. Clinical data showed Paxlovid reducing Covid hospitalization and death by 89%. It was nominated for November’s cover by Mike Koehler [...]

This month’s cover molecule, Pfizer’s PF-07321332 (nirmatrelvir, API of Paxlovid) is an oral, reversible covalent SARS-CoV-2 main protease inhibitor, which has been submitted to the FDA by Pfizer for emergency approval for Covid treatment. Interim data showed Paxlovid reducing Covid hospitalization and death by 89%. It was nominated for this month’s [...]

The Gilead SARS-CoV-2 drug, GS-621763, is an oral prodrug of the parent nucleoside of remdesivir (GS-441524) which demonstrated therapeutic and prophylactic efficacy in a ferret model of SARS-CoV-2 infection, significantly reducing viral load to near-undetectable levels with twice-daily administration. Remdesivir is already FDA [...]

The Merck Institute antimalarial compound, M5717, is the first plasmodium eEF2 inhibitor to reach clinical development, and is a good example of an orally available dibasic compound as well as an antimalarial with a discrete target identified after traditional phenotypic screening. It was well-tolerated in healthy volunteers and has a [...]

The Janssen pan-genotype, pan-serotype dengue virus inhibitor, JNJ-A07 , demonstrates broad activity against a panel of 21 clinical isolates and has a high barrier to resistance. It blocks the interaction between the non-enzymatic NS4B protein and NS3, preventing them from forming an NS3-NS4B complex which is essential for replication (though [...]

The Entasis broad-spectrum antibiotic, ETX0462 , is both an inhibitor of penicillin-binding proteins (PBPs, the target of beta-lactams) and a beta-lactamase inhibitor (BLI). Reviewer Mike Koehler thought this was a substantial disclosure. “A number of BLIs co-formulated with carbapenems and monobactams are currently on the market. There are a [...]

Merck anion-dependent farnesyl transferase inhibitor

AL-611 is a prodrug to a nucleoside inhibitor of HCV NS5B polymerase. While there have been very successful nucleoside drugs (e.g. sofosbuvir), several nucleoside inhibitors of HCV previously failed in the clinic due to severe toxicities, in some cases due to incorporation of the nucleosides into host RNA. The Janssen Biopharma (formerly [...]

“compound 9” is an investigational prodrug of pibrentasvir (ABT-530), a key component of AbbVie’s marketed HCV combination Mavyret. Pibrentasvir (PIB) is the largest approved oral small molecule since 1983 (MW = 1113, not including the peptide semaglutide at MW = 4113), and came with some solubility issues (aq. sol. pH 7 = <0.0001 mg/mL). The [...]

GS-6207 is an HIV-1 inhibitor that acts on the capsid protein monomer (p24), which normally self-assembles in the HIV virion to form the capsid core that is essential for virus infectivity. GS-6207 targets a protein-protein interaction between the small (24 kDa) p24 monomers, binding in a glue-like fashion to two separate monomers, and is [...]

LXE408 is an oral antileishmanarial compound that selectively targets the kinetoplastid proteosome vs. the mammalian proteosome. The prior candidate, GNF6702, had solubility-limited oral absorption, which could have been addressed with a specialized formulation but would have increased the cost and limited use in developing countries. A [...]

ETX0282 is an oral prodrug of a class A, C, and D serine β-lactamase inhibitor in clinical development for drug-resistant enterobacterial infections in combination with the beta-lactam drug cefpodoxime proxetil. Impressively ETX0282 had no observed adverse effect levels (NOAELs) of 500 mg/kg/day and 400 mg/kg/day in rat and dog, respectively, [...]

“Compound 10” is a potent and selective inhibitor of Class I histone deacetylases (HDAC1/2/3) which increases HIV activity in treatment-suppressed patient immune cells for the goal of eradicating HIV from latent reservoirs. Fascinatingly, the compound 10 actually binds to a zinc ion in the HDAC proteins through a ketone hydrate, formed in [...]

JNJ-53718678 is a potent and orally available fusion inhibitor of the RSV virus, optimized from a prior oral inhibitor, BMS-433771. The prior inhibitor was challenged by moderate potency, suboptimal PK in preclinical species, limited lung distribution, and potential complications from CYP TDI due to an aminocyclopropyl moiety. The improved [...]

ASP5286 is an analog of the natural product cyclosporin A that maintains the anti-HCV activity of cyclosporin A by binding to cyclophilin, but was optimized to be less immunosuppresive than cyclosporin A. The macrocycle was identified through semisynthetic derivitization of a related natural product, FR901459. The Astellas team was able to [...]

MK-5204 is a broad spectrum Candida antifungal agent derived from the natural product, enfumafungin. I was impressed that the molecule not only demonstrates oral efficacy but also has good oral PK in higher species (dog, cyno), given that the molecule is a large zwitterion with several very polar groups, including a primary amide, primary [...]

GSK2818713 is an HCV NS5A replication complex inhibitor with an interesting biphenylene linker. The crowded, hotly competitive NS5A space has led to a lot of creative chemical scaffolds including this one.

QPX7728 is an ultrabroad-spectrum beta-lactamase inhibitor with activity against both serine and zinc metallo-beta-lactamases, in contrast to approved beta-lactamase inhibitors such as relebactam which are only active against serine metalloproteases. Interestingly, the boron of the molecule coordinates to serine hydroxyl groups in serine [...]

We asked the global drug discovery community to vote on their favorite molecule from 2020, and the results are in. The community’s 2020 choice for Small Molecule of the Year is GS-6207 (lenacapavir), the awe-inspiring HIV capsid inhibitor published by Gilead Sciences in a 2020 issue of Nature.