Discovery of ZN-c3, a Highly Potent and Selective Wee1 Inhibitor Undergoing Evaluation in Clinical Trials for the Treatment of Cancer.

Wee1 inhibition has received great attention in the past decade as a promising therapy for cancer treatment. Therefore, a potent and selective Wee1 inhibitor is highly desirable. Our efforts to make safer and more efficacious Wee1 inhibitors led to the discovery of compound 16, a highly selective Wee1 inhibitor with balanced potency, ADME, and pharmacokinetic properties. The chiral ethyl moiety of compound 16 provided an unexpected improvement of Wee1 potency. Compound 16, known as ZN-c3, showed excellent in vivo efficacy and is currently being evaluated in phase 2 clinical trials.

Evaluation of KP-1199: a novel acetaminophen analog for hemostatic function and antinociceptive effects.

BACKGROUND: Acetaminophen (APAP) is a widely self-prescribed analgesic for mild to moderate pain, but overdose or repeat doses can lead to liver injury and death. Kalyra Pharmaceuticals has developed a novel APAP analog, KP-1199, currently in Phase 1 clinical studies, which lacks hepatotoxicity. In this study, the authors evaluated the antinociceptive effect of KP-1199 on thermal injury-induced nociceptive behaviors as well as hemostatic parameters using human blood samples. METHODS: Full-thickness thermal injury was induced in anesthetized adult male Sprague-Dawley rats. On day 7 post-injury, KP-1199 (30 and 60 mg/kg) or APAP (60 mg/kg) was administered orally. Antinociception of KP-1199 and APAP were assessed at multiple time points using Hargreaves' test. In separate experiments, human whole blood was collected and treated with either KP-1199, APAP, or Vehicle (citrate buffer) at 1× (214 µg/ml) and 10× (2140 µg/ml) concentrations. The treated blood samples were assessed for: clotting function, thrombin generation, and platelet activation. RESULTS: APAP did not produce antinociceptive activity. KP-1199 treatment significantly increased the nociceptive threshold, and the antinociceptive activity persisted up to 3 h post-treatment. In human samples, 10× APAP caused significantly prolonged clotting times and increased platelet activation, whereas KP-1199 had caused no negative effects on either parameter tested. CONCLUSION: These results suggest that KP-1199 possesses antinociceptive activity in a rat model of thermal injury. Since KP-1199 does not induce platelet activation or inhibit coagulation, it presents an attractive alternative to APAP for analgesia, especially for battlefield or surgical scenarios where blood loss and blood clotting are of concern.

Acid-Induced Liberation of Polysubstituted Cyclopentadiene Ligands from Cyclopentadienyl Cobalt: A [2 + 2 + 1] Cycloaddition Route toward 1,2,4-Trisubstituted Cyclopentadienes.

Here, we report that trifluoroacetic acid (TFAH) induces demetallation and protodesilylation of the cyclopentadiene ligand in cobalt-η4-cyclopentadiene complexes of general formula [(η5-C5H5)Co(η4-exo-C(TMS)═C(SO2Ph)CH═CRCH(CO2Et))] (1-Ph, R = Ph; 1-ArtBu, R = p-C6H4tBu; 1-ArNMe2, R = p-C6H4NMe2; and 1-Me, R = Me). The trisubstituted cyclopentadiene products are isolated as a mixture of two tautomers, [(CH2C(SO2Ph)═CHC(CO2Et)═CR)] (8-R-A) and [(CH═C(SO2Ph)CH2C(CO2Et)═CR)] (8-R-B). The endo isomer, [(η5-C5H5)Co(η4-endo-C(TMS)═C(SO2Ph)CH═CPhCH(CO2Et))] (1-Ph-endo), also undergoes demetallation and protodesilylation to give 8-Ph-A and 8-Ph-B in excellent yield. The cobalt-cyclopentadiene complex, [(η5-C5H5)Co(η4-exo-C(TMS)═C(SO2Ph)CH═C(CO2Me)CH(CO2Et))] (1-CO2Me), undergoes demetallation and protodesilylation upon treatment with TFAH to give a hydrogen-bonded fulvenol (8-CO2Me). Liberation of the ethoxy-substituted cyclopentadiene ligand of [(η5-C5H5)Co(η4-exo-C(TMS)═C(SO2Ph)CH═C(OEt)CH(CO2Et))] (1-OEt) leads to formation of a cyclopentenone derivative (11). Thermolysis of 8-Ph-A/8-Ph-B in the presence of maleimide leads to a highly functionalized Diels-Alder adduct, whereas 8-Ph-A/8-Ph-B serves as precursors to trisubstituted ruthenocenes by in situ deprotonation and reaction with [(η5-C5R5)Ru(NCMe)3]PF6 (16-H, R = H; 16-Me, R = Me).

Design of potent and selective inhibitors to overcome clinical anaplastic lymphoma kinase mutations resistant to crizotinib.

Crizotinib (1), an anaplastic lymphoma kinase (ALK) receptor tyrosine kinase inhibitor approved by the U.S. Food and Drug Administration in 2011, is efficacious in ALK and ROS positive patients. Under pressure of crizotinib treatment, point mutations arise in the kinase domain of ALK, resulting in resistance and progressive disease. The successful application of both structure-based and lipophilic-efficiency-focused drug design resulted in aminopyridine 8e, which was potent across a broad panel of engineered ALK mutant cell lines and showed suitable preclinical pharmacokinetics and robust tumor growth inhibition in a crizotinib-resistant cell line (H3122-L1196M).

Scalable synthesis of 1-bicyclo[1.1.1]pentylamine via a hydrohydrazination reaction.

The reaction of [1.1.1]propellane with di-tert-butyl azodicarboxylate and phenylsilane in the presence of Mn(dpm)(3) to give di-tert-butyl 1-(bicyclo[1.1.1]pentan-1-yl)hydrazine-1,2-dicarboxylate is described. Subsequent deprotection gives 1-bicyclo[1.1.1]pentylhydrazine followed by reduction to give 1-bicyclo[1.1.1]pentylamine. The reported route marks a significant improvement over the previous syntheses of 1-bicyclo[1.1.1]pentylamine in terms of scalability, yield, safety, and cost.

2-Chloro-4-(1H-pyrazol-1-yl)-5-(trifluoro-meth-yl)pyrimidine.

The reaction of 2,4-dichloro-5-(trifluoro-meth-yl)pyrimidine with 1H-pyrazole gave two structural isomers in a 1:1 ratio that were separable by chromatography. The title compound, C(8)H(4)ClF(3)N(4), was the first product to elute and was characterized in the present study to confirm that substitution by the pyrazolyl group had occurred at position 4. The mol-ecule (with the exception of the F atoms) is essentially planar, with a mean deviation of 0.034 Šfrom the least-squares plane through all non-H and non-F atoms. The bond angles in the pyrimidine ring show a pronounced alternating pattern with three angles, including those at the two N atoms being narrower, and the remaining three wider than 120°.

4-Chloro-7-hydr-oxy-6-methyl-1,7-naphthyridin-8(7H)-one.

The title compound, C(9)H(7)ClN(2)O(2), was prepared by reaction of methyl 4-chloro-3-(prop-1-yn-yl)picolinate with hydroxy-l-amine in MeOH/KOH solution. The two essentially planar mol-ecules which make up the asymmetric unit have almost identical geometries and and are linked into dimeric aggregates via pairs of O-H⋯O hydrogen bonds. These aggregates have almost perfect inversion symmetry; however, quite unusually, the inversion center of the dimer does not coincide with the crystallographic inversion center.

Reactions of a metallacyclobutene complex with alkenes.

The first productive reactions of a characterized metallacyclobutene complex with alkenes are reported. Thus, the metallacyclobutene complex (eta5-C5H5)(PPh3)Co[kappa2-(C,C)-C(SO2Ph) C(Si(CH3)3)CH(CO2CH2CH3)] (2) undergoes reaction with alkenes to give 1,4-diene complexes with a high degree of regio- and stereoselectivity. A mechanism is proposed in which the metallacyclobutene generates a cyclic vinylcarbene intermediate that undergoes [4 + 2]-cycloaddition reactions with activated alkenes. A model of the vinylcarbene intermediate has been examined using quantum mechanical methods.

3-Amino-5-bromo-2-iodo-pyridine.

The reaction of 3-amino-5-bromo-pyridine with N-iodo-succinimide in the presence of acetic acid produces the title compound, C(5)H(4)BrIN, with an iodo substituent in position 2 of the pyridine ring. The crystal structure features rather weak inter-molecular N-H⋯N hydrogen bonds linking the mol-ecules into chains along the z axis of the crystal.

Sulfoxide carbon-sulfur bond activation.

The alkynylsulfoxide, TMSCCSO(p-tolyl) (TMS = trimethylsilyl, tolyl = C6H4Me), undergoes reaction with (eta5-C5H5)Co(PPh3)2 at room temperature to give the cobaltosulfoxide complex, (C5H5)Co(PPh3)(eta1-CCTMS)[eta1-(S)-SO(p-tolyl)], which was characterized by X-ray crystallography. Exposure of this cobaltosulfoxide complex to oxygen gas leads to the formation of the corresponding metallosulfone complex, (C5H5)Co(PPh3)(eta1-CCTMS)[eta1-(S)-SO2(p-tolyl)], which was characterized by X-ray crystallography. Alternatively, in solution at room temperature, the metallosulfoxide is converted to a 1:4 mixture of the equatorial-equatorial and equatorial-axial bridging cobalt-thiolato dimers, {(C5H5)Co[mu-S(p-tolyl)]}2, respectively. The equatorial-equatorial isomer was characterized by X-ray crystallography.

Ring-strain effects on the oxidation potential of enediynes and enediyne complexes.

The metal-enediyne complexes [(eta 5-C5H5)Fe[eta 5-1,2-C5H3C identical to C(CH2)nC identical to]] (4, n = 4; 5, n = 5) and [(eta 5-C5H5)-Fe[eta 5-1,2-C5H3(C identical to C Me)2]] (6) were prepared from 1,2-diethynylferrocene (3). Complexes 4 and 5 were characterized in the solid state by X-ray crystallographic analysis. The structures of 4 and 6 were determined by computation using ab initio methods. A correlation was observed between ring-strain and increased ease of electrochemical oxidation along the series 6 (+0.164 V) to 5(+0.152 V) to 4 (+0.123 V). A similar trend in ionization potentials was identified in both the gas phase and in solution by computational methods.