Context. BMS-986176/LX-9211 (BMS) is an oral, CNS-penetrable AAK1 kinase inhibitor being developed for treatment of neuropathic pain . There are six main classes of pain medications, NSAIDs, opioids, ion channel modulators, serotonergic, monoaminergic, and GABAnergic drugs that are broadly used for pain in general, but neuropathic pain due to [...]

Context. Branaplam (Novartis Institutes for Biomedical Research) is an oral brain-penetrant splicing modulator, originally developed as a small molecule splicing modulator for spinal muscular atrophy (SMA). It turns out to also lower huntingtin levels and is being developed (with Fast Track Designation ) for patients with Huntington’s Disease [...]

Context. MAK683 is an oral, allosteric and selective PRC2 inhibitor intended for PRC2-dependent cancers . PRC2 is an essential epigenetic regulator of gene expression and enhanced or diminished PRC2 function have been implicated in a number of cancers . Enhancer of zeste homolog 2 (EZH2), one of the four core components of PRC2 that directly [...]

Context. HR1405-01 (Nanjing Heron Pharmaceutical) is an intravenous NSAID with inflammatory and analgesic activities. Oral NSAIDs (ibuprofen, naproxen..) are widely used, and it is interesting to see justification for a new intravenous NSAID. Intravenous ibuprofen was the first intravenous NSAID to be approved, following which a couple of [...]

Small-molecule drug candidates are increasingly falling “ beyond the rule of 5 ,” making oral administration more challenging. Optimizing a drug’s solid form can improve its solubility and bioavailability when further molecular modifications are prohibitive. This minireview covers solid form strategies for increasing the solubility and oral [...]

One of the privileges that have come with building Drug Hunter has been all the insightful thoughts and commentary our readers share. We also appreciate how readers help catch mistakes and offer corrections. This new series of “ Drug Hunter Letters” highlights recent insightful communications from drug hunters, which includes this time: Dr [...]

There were six small molecule candidates disclosed on Apr. 10th at AACR New Orleans 2022 at the New Drugs on the Horizon session, with another four on Apr. 11th. The New Drugs on the Horizon session is organized by the Chemistry in Cancer Research (CICR) Working Group , this year chaired by Joachim Rudolph . Thanks to reviewer Julien Lefranc [...]

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 [...]

The ACS first disclosures from ACS Spring 2022 MEDI section included six molecules, summarized below. Together with industry veteran Jesse Keicher , we put these molecules in context, exploring what makes each molecule interesting to drug hunters beyond what was shared at the conference. The first disclosures were: AMG 650, Amgen’s kinesin [...]

This article reviews the three novel drugs approved by the FDA in March 2022 in detail. together with Dr. Naveed Yasin, Jesse Keicher, Dr. Jennifer Huen, and Dr. Adrian Parodi Small molecules: Ztalmy ® ( ganaxolone ): An oral GABAA receptor positive allosteric modulator to treat seizures in cyclin-dependent kinase-like 5 deficiency disorder [...]

Drug Hunter’s April 2022 edition of Molecules of the Month features some emerging small molecule clinical candidates as well as several interesting molecules in preclinical stages for a broad range of indications. Among these are two KRASG12C inhibitors, JDQ443 from Novartis and AZD4625 from AstraZeneca, each with unique chemical structure and binding modes, which set them apart in the highly competitive KRASG12C research space. Several of the featured compounds made their debut this month, with both well-established targets, such as the Nav1.7/1.8 blocker ABBV-318 from AbbVie, and emerging ta...

The FDA approved five novel small molecule drugs in neurology in 2021. Addressing a range of conditions from ADHD to relapsing MS, the 2021 neurology drug approvals are: atogepant (Qulipta): calcitonin gene-related peptide (CGRP) receptor antagonist ponsimod (Ponvory): selective sphingosine-1-phosphate (S1P) receptor 1 (S1PR1) modulator [...]

Context. BMS-820132 (Bristol Myers Squibb) is an oral glucokinase (GK) partial activator intended for diabetes. GK activators for diabetes were hotly pursued in the late 2000’s, with well over 100 industry patents on GK activators by 2009. The pursuit was triggered by the discovery of the first allosteric activators of glucokinase from an [...]

Context. LY3154885 (Eli Lilly and Company) is an oral D1 modulator. Lilly recently completed several clinical trials with LY3154207 ( mevidalen ), the first D1 positive allosteric modulator (D1PAM) with published clinical data, in Parkinson’s disease ( NCT02562768 ), sleep ( NCT02603861 ), and lewy body dementia (LBD) ( NCT03305809 ). In [...]

Context. Danavorexton (Takeda, TAK-925) is a CNS-penetrant, injectable OX2 agonist. Orexin receptor (OX1/OX2) antagonists (e.g. daridorexant ) are approved for treatment of insomnia. Orexin agonism would be expected to have the opposite effect, promoting wakefulness rather than sleep, which is helpful for patients with narcolepsy (difficulty [...]

Context. ASP5878 (Astellas Pharma Inc.) is an oral pan-FGFR inhibitor. The four FGFRs have emerged as attractive targets for cancer in recent years, and we’ve covered several recently. FGFR3 has had less dedicated effort disclosed on it specifically relative to FGFRs 1, 2, and 4, but genetic alterations of FGFR3 have been noted in bladder [...]

Compound 14f (Kyowa Kirin) is an oral ChemR23 inhibitor with two acidic sites. Nominated by Bryan McKibben , this article describes a scaffold hopping exercise to address the short half-life of previously described chemical matter, and the successful development of in-vivo tool inhibitors to probe ChemR23 biology in animal models of [...]

Context. GCC5694A (GC Pharma (Green Cross)) is an oral SGLT2 inhibitor. SGLT2 inhibitors help glycemic control in diabetes by preventing reabsorption of glucose in the kidney. Dapagliflozin was the first SGLT2 inhibitor approved in the EU (2012), and canagliflozin was the first to be approved in the US (2013). We recently highlighted [...]