Gamcemetinib (10-12-9) Physical and Chemical Properties
Gamcemetinib
Investigational heterocyclic small‑molecule pharmaceutical API supplied for clinical‑stage development, medicinal chemistry and analytical characterization in R&D and formulation workstreams.
| CAS Number | 10-12-9 |
| Family | Heterocyclic small molecule (thieno-diazepino scaffold) |
| Typical Form | Powder or crystalline solid |
| Common Grades | EP |
Gamcemetinib is a synthetic, small-molecule pharmaceutical candidate built on a fused polyheterocyclic scaffold that includes thiophene- and diazepine-like rings fused to a quinoline-type core and a substituted pyrimidine ether. The architecture contains multiple heteroatoms (N, O, S, Cl) and a single defined stereocenter, producing a compact but conformationally constrained polycyclic framework. Key structural motifs are an aryl–heteroaryl ether linkage to a 2-chloro-5-(ethoxymethyl)pyrimidinyl fragment, a lactam-like carbonyl within the fused ring system, and an embedded thieno-quinoline substructure; these features combine substantial aromatic surface area with polarized heteroatom functionality.
Electronically the molecule presents mixed characteristics: a relatively high computed lipophilicity (XLogP \(\;4.5\)) arising from extensive conjugated aromatic rings and limited aliphatic surface, counterbalanced by significant polar character from multiple hydrogen-bond acceptors (8) and two hydrogen-bond donors. The topological polar surface area (TPSA) is reported as 127 \(\text{Å}^2\), consistent with appreciable polarity and potential for H-bonding that can reduce passive membrane permeation despite overall lipophilicity. The formal charge is neutral in the covalent form; basic heterocycles present may be weakly ionizable under strongly acidic conditions but no experimental pKa values are available here.
From an applied perspective, Gamcemetinib is an investigational active pharmaceutical ingredient (API) developed for clinical indications; its utility derives from the rigid heterocyclic scaffold and functionalization that support specific target engagement in biological systems. The combination of moderate-to-high lipophilicity and elevated polar surface area influences formulation considerations (e.g., solubilization strategies) and ADME-related behavior (permeability, plasma protein binding). Common commercial grades reported for this substance include: EP.
Basic Physicochemical Properties
Density and Solid-State Form
No experimentally established value for this property is available in the current data context.
Qualitatively, the multi-ring, highly conjugated structure and molecular weight suggest Gamcemetinib is an organic crystalline solid under standard handling conditions. Solid-state form (polymorphism, solvate/hydrate tendency) is not reported here but should be characterized during development because the dense aromatic packing and heteroatom pattern can lead to multiple crystalline forms and potentially solvated crystals.
Melting Point
No experimentally established value for this property is available in the current data context.
Melting behavior for polycyclic heteroaromatic APIs is often sensitive to polymorphism and crystal lattice energy; dedicated DSC/XRD analysis is recommended during preformulation.
Solubility and Dissolution Behavior
No experimentally established aqueous solubility values are available in the current data context.
Qualitatively, the combination of computed lipophilicity (\(\mathrm{XLogP}=4.5\)), a large aromatic surface, and a TPSA of 127 \(\text{Å}^2\) is consistent with limited intrinsic aqueous solubility. The presence of two hydrogen-bond donors and multiple acceptors increases polarity but is often insufficient to overcome the hydrophobic surface area for spontaneous dissolution. In formulation development, common approaches for compounds with this profile include cosolvents, surfactant-based dispersion, micronization or amorphous solid dispersions, and salt or prodrug strategies where chemically feasible; selection should follow experimental solubility and stability screening.
Chemical Properties
Acid–Base Behavior and Qualitative pKa
No experimentally established value for this property is available in the current data context.
Qualitatively, Gamcemetinib contains heterocyclic nitrogen atoms that can act as weak bases and oxygen functionalities that are not significantly acidic under normal conditions. The molecule is formally neutral (formal charge 0) in its unprotonated covalent form. Any relevant ionization in aqueous media would most likely be limited to protonation of basic heterocycles under strongly acidic conditions; therefore, at physiological pH the molecule is expected to be largely unionized.
Reactivity and Stability
The structural framework contains electronically stable aromatic heterocycles and a lactam-like carbonyl embedded in a fused polycyclic system, conferring overall chemical stability toward mild conditions. Labile points to consider are the aryl–heteroaryl ether bond linking the pyrimidine substituent and the ethoxymethyl side chain, which can be susceptible to cleavage under strongly acidic or nucleophilic conditions. The presence of a sulfur-containing heterocycle and electron-rich aromatic rings can make the scaffold more prone to oxidative transformations under harsh oxidative conditions. Standard development precautions include avoidance of strong acids/bases and oxidants and assessment of hydrolytic and oxidative degradation pathways under ICH-relevant stress conditions.
Molecular Parameters
Molecular Weight and Formula
- Molecular formula: C22H20ClN5O3S
- Molecular weight: \(469.9\) g·mol^{-1}
- Exact/Monoisotopic mass: \(469.0975384\)
These values reflect a high molecular-weight small molecule by drug-like standards and will influence formulation, dosing strategy, and analytical method sensitivity.
LogP and Structural Features
- Computed lipophilicity: XLogP3-AA = \(4.5\)
- Topological polar surface area (TPSA): \(127\) \(\text{Å}^2\)
- Hydrogen-bond donors: 2
- Hydrogen-bond acceptors: 8
- Rotatable bond count: 5
- Formal charge: 0
- Defined atom stereocenter count: 1
- Heavy atom count: 32
- Complexity: 677
Interpretation: the computed XLogP indicates moderate-to-high lipophilicity, which favors membrane partitioning and potential high plasma protein binding but can reduce aqueous solubility. The TPSA of \(127\) \(\text{Å}^2\) and multiple polar heteroatoms imply significant polar surface and hydrogen-bonding capacity that may limit passive permeability. A rotatable bond count of 5 and a single stereocenter indicate a relatively rigid and stereochemically defined scaffold, which is favorable for selective target binding but may complicate stereospecific synthesis and analytical control.
Structural Identifiers (SMILES, InChI)
- SMILES: CCOCC1=CN=C(N=C1OC2=NC3=C(C=C2)C4=C(C=C3)SC5=C4NCC@HC)Cl
- InChI: InChI=1S/C22H20ClN5O3S/c1-3-30-10-12-9-25-22(23)28-21(12)31-16-7-4-13-14(27-16)5-6-15-17(13)18-19(32-15)20(29)26-11(2)8-24-18/h4-7,9,11,24H,3,8,10H2,1-2H3,(H,26,29)/t11-/m1/s1
- InChIKey: PYOQIOLRFIRRSO-LLVKDONJSA-N
These identifiers should be used for unambiguous electronic matching, cheminformatics workflows, and registration purposes.
Identifiers and Synonyms
Registry Numbers and Codes
- CAS number: 10-12-9
- UNII: OS2IR8TV1O
- ChEMBL ID: CHEMBL5314585
- KEGG ID: D12560
- NCI Thesaurus Code: C199205
- InChIKey: PYOQIOLRFIRRSO-LLVKDONJSA-N
- IUPAC name (computed): (15R)-5-[2-chloro-5-(ethoxymethyl)pyrimidin-4-yl]oxy-15-methyl-11-thia-6,14,17-triazatetracyclo[8.8.0.02,7.012,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one
Note: the CAS number presented here is the registry string associated with this entry.
Synonyms and Brand-Independent Names
Available synonyms and alternative identifiers reported include: - Gamcemetinib - CC-99677 - BMS-986371 - Gamcemetinib (USAN) - gamcemetinib (INN) - DA-72008 - MS-28693 - (10R)-3-{[2-chloro-5-(ethoxymethyl)pyrimidin-4-yl]oxy}-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-8-one - orb1691401 - RefChem:1085680 (Additional depositor and registry synonyms exist; the most commonly used nonproprietary name is Gamcemetinib.)
Industrial and Pharmaceutical Applications
Role as Active Ingredient or Intermediate
Gamcemetinib is described as an investigational small-molecule therapeutic candidate with clinical development activity reaching Phase II for multiple indications. As such, its primary industrial role is as an active pharmaceutical ingredient (API) in preclinical and clinical development programs rather than as a commodity chemical or bulk intermediate.
Formulation and Development Contexts
In formulation and development, Gamcemetinib will be addressed as a poorly soluble, moderately lipophilic API with high aromatic content and substantial polar surface. Typical development tasks include selection of an appropriate solid-state form, solubilization strategy, chromatographic method development for assay and impurity profiling, and evaluation of chemical stability under stress conditions. No specific formulation compositions or clinical formulations are reported here; practical formulation choices will follow experimental solubility, stability, and pharmacokinetic data.
Specifications and Grades
Typical Grade Types (Pharmaceutical, Analytical, Technical)
Typical grade categories relevant to substances in pharmaceutical development include: - Pharmaceutical (API) grade — appropriate for clinical and commercial dosing formulations, manufactured under GMP and subject to strict impurity and residual solvent controls. - Analytical grade — high purity for use in method development, reference standards, and QC testing. - Technical grade — for nonclinical research and early-stage screening where impurity profiles are of lower regulatory concern.
Explicit reported commercial grade for this substance: EP.
General Quality Attributes (Qualitative Description)
Quality attributes to be specified for development and procurement include chemical identity (structure, stereochemistry), assay purity, residual solvents, impurity profile (process and degradation impurities), enantiomeric excess (if relevant), and water content or solvate form. For an API candidate of this complexity, attention to stereochemical specification, control of residual reagents from heterocycle construction, and detection of sulfur- and nitrogen-containing impurities is important. Detailed numeric specification limits are not provided here and must be defined during formal specification setting.
Safety and Handling Overview
Toxicological Profile and Exposure Considerations
No quantitative toxicological endpoints (e.g., LD50, NOAEL) are reported in the current data context.
Qualitatively, Gamcemetinib is a bioactive investigational pharmaceutical candidate and should be treated as a potential systemic toxicant until specific toxicology data are available. Standard laboratory precautions for APIs are appropriate: minimize dust generation, avoid inhalation and dermal exposure, and use appropriate engineering controls (local exhaust or containment) during milling, weighing, or synthetic operations. Use gloves, eye protection, and protective clothing. Assume potential sensitization, irritancy, and systemic effects consistent with small-molecule pharmacology until safety data indicate otherwise. For detailed hazard, transport and regulatory information, users should refer to the product-specific Safety Data Sheet (SDS) and local legislation.
Storage and Handling Guidelines
Store in a cool, dry place in tightly closed containers protected from strong oxidants and extremes of pH. Controlled room temperature or refrigerated storage may be recommended based on stability data generated during development; for long-term storage, solid-state characterization (polymorph, hydrate/solvate status) should guide conditions. Protect from light if photo-degradation pathways are identified. Implement standard spill control and waste disposal procedures consistent with hazardous pharmaceutical substances and institutional guidelines.
