ABSTRACT
The design and synthesis of indazolinone containing kinase inhibitors are reported. Regioisomers that showed profound potency variation in previously-reported isoindolinone and aminoindazole systems were surprisingly found to have similar potencies in the case of the indazolinone chemical series. An interpretation using differential hinge hydrogen bonding and tautomeric equilibrium of indazolinone ring system is supported by quantum mechanics calculations. The equipotent inhibition of a representative kinase (KDR) by regioisomeric indazolinones 4 and 5 is clear evidence that in case of the indazolinone hinge, both tautomers are equally favored, and should be considered in design of inhibitors.
Subject(s)
Indazoles/chemical synthesis , Protein Kinase Inhibitors/chemical synthesis , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Indazoles/pharmacology , Isomerism , Models, Molecular , Molecular Structure , Protein Kinase Inhibitors/pharmacology , Structure-Activity RelationshipABSTRACT
Seeking compounds preferentially potent and selective for MMP-13, we reported in the preceding Letter on a series of hydroxamic acids with a flexible benzamide tail groups.(1a) Here, we replace the amide moiety with non-hydrolyzable heterocycles in an effort to improve half-life. We identify a hydroxamate tetrazole 4e that spares MMP-1 and -14, shows >400-fold selectivity versus MMP-8 and >600-fold selectivity versus MMP-2, and has a 4.8 h half-life in rats. X-ray data (1.9 Å) for tetrazole 4c is presented.
Subject(s)
Amides/chemical synthesis , Enzyme Inhibitors/chemical synthesis , Heterocyclic Compounds/chemical synthesis , Hydroxamic Acids/chemical synthesis , Matrix Metalloproteinase Inhibitors , Sulfones/chemical synthesis , Amides/chemistry , Animals , Crystallography, X-Ray , Enzyme Inhibitors/chemistry , Heterocyclic Compounds/chemistry , Hydroxamic Acids/chemistry , Matrix Metalloproteinase 13/chemistry , Models, Molecular , Rats , Structure-Activity Relationship , Substrate Specificity , Sulfones/chemistryABSTRACT
α-Sulfone-α-piperidine and α-tetrahydropyranyl hydroxamates were explored that are potent inhibitors of MMP's-2, -9, and -13 that spare MMP-1, with oral efficacy in inhibiting tumor growth in mice and left-ventricular hypertrophy in rats and in the bovine cartilage degradation ex vivo explant system. α-Piperidine 19v (SC-78080/SD-2590) was selected for development toward the initial indication of cancer, while α-piperidine and α-tetrahydropyranyl hydroxamates 19w (SC-77964) and 9i (SC-77774), respectively, were identified as backup compounds.
Subject(s)
Anti-Inflammatory Agents/chemical synthesis , Antineoplastic Agents/chemical synthesis , Cardiovascular Agents/chemical synthesis , Hydroxamic Acids/chemical synthesis , Matrix Metalloproteinase Inhibitors , Piperidines/chemical synthesis , Pyrans/chemical synthesis , Sulfones/chemical synthesis , Animals , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Biological Availability , Cardiovascular Agents/chemistry , Cardiovascular Agents/pharmacology , Cartilage, Articular/drug effects , Cartilage, Articular/pathology , Cattle , Crystallography, X-Ray , Humans , Hydroxamic Acids/chemistry , Hydroxamic Acids/pharmacology , Hypertrophy, Left Ventricular/drug therapy , Macaca fascicularis , Mice , Mice, Nude , Models, Molecular , Molecular Structure , Piperidines/chemistry , Piperidines/pharmacology , Pyrans/chemistry , Pyrans/pharmacology , Rats , Structure-Activity Relationship , Sulfones/chemistry , Sulfones/pharmacology , Xenograft Model Antitumor AssaysABSTRACT
A series of pyrrolizidine esters, amides, and ureas was prepared and tested for 5-HT(4) and 5-HT(3) receptor binding, 5-HT(4) receptor agonism in the rat tunica muscularis mucosae (TMM) assay, and for 5-HT(3) receptor-mediated functional antagonism in the Bezold-Jarisch reflex assay. Several pyrrolizidine derivatives were identified with high affinity for the 5-HT(4) receptor, including benzamide 12a (SC-53116), a potent and selective 5-HT(4) partial agonist that exhibits efficacy in promoting antral contractions and activity in promoting gastric emptying in canine models. Also discovered were 5-HT(4) receptor antagonists, including imidazopyridine amide 12h (SC-53606), which is a potent and selective 5-HT(4) receptor antagonist with a pA(2) value of 8.13 in the rat TMM assay. N-Methyl indole ester 13d was identified as a potent 5-HT(4) antagonist with a pA(2) value of 8.93. High selectivity was observed for these pyrrolizidine derivatives versus other monoamine receptors, including 5-HT(1), 5-HT(2), D(1), D(2), alpha(1), alpha(2), and beta receptors.
Subject(s)
Amides/chemical synthesis , Benzamides/chemical synthesis , Imidazoles/chemical synthesis , Indoles/chemical synthesis , Pyrroles/chemical synthesis , Pyrrolizidine Alkaloids/chemical synthesis , Serotonin 5-HT4 Receptor Agonists , Serotonin 5-HT4 Receptor Antagonists , Amides/chemistry , Amides/pharmacology , Animals , Benzamides/chemistry , Benzamides/pharmacology , Bradycardia/prevention & control , Brain/drug effects , Brain/metabolism , Dogs , Esophagus/drug effects , Esophagus/physiology , Esters/chemical synthesis , Esters/chemistry , Esters/pharmacology , Female , Gastric Emptying/drug effects , Guinea Pigs , Imidazoles/chemistry , Imidazoles/pharmacology , In Vitro Techniques , Indoles/chemistry , Indoles/pharmacology , Male , Mice , Muscle Contraction/drug effects , Muscle, Smooth/drug effects , Muscle, Smooth/physiology , Pyloric Antrum/drug effects , Pyloric Antrum/physiology , Pyrroles/chemistry , Pyrroles/pharmacology , Pyrrolizidine Alkaloids/chemistry , Pyrrolizidine Alkaloids/pharmacology , Radioligand Assay , Rats , Rats, Wistar , Structure-Activity RelationshipABSTRACT
alpha-Piperidine-beta-sulfone hydroxamate derivatives were explored that are potent for matrix metalloproteinases (MMP)-2, -9, and -13 and are sparing of MMP-1. The investigation of the beta-sulfones subsequently led to the discovery of hitherto unknown alpha-sulfone hydroxamates that are superior to the corresponding beta-sulfones in potency for target MMPs, selectivity vs MMP-1, and exposure when dosed orally. alpha-Piperidine-alpha-sulfone hydroxamate 35f (SC-276) was advanced through antitumor and antiangiogenesis assays and was selected for development. Compound 35f demonstrates excellent antitumor activity vs MX-1 breast tumor in mice when dosed orally as monotherapy or in combination with paclitaxel.
Subject(s)
Antineoplastic Agents/chemical synthesis , Hydroxamic Acids/chemical synthesis , Matrix Metalloproteinase Inhibitors , Piperidines/chemical synthesis , Sulfones/chemical synthesis , Administration, Oral , Angiogenesis Inhibitors/chemical synthesis , Angiogenesis Inhibitors/chemistry , Angiogenesis Inhibitors/pharmacology , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Female , Hydroxamic Acids/chemistry , Hydroxamic Acids/pharmacology , Mammary Neoplasms, Experimental/drug therapy , Mammary Neoplasms, Experimental/mortality , Mice , Mice, Nude , Paclitaxel/therapeutic use , Piperidines/chemistry , Piperidines/pharmacology , Structure-Activity Relationship , Sulfones/chemistry , Sulfones/pharmacology , Xenograft Model Antitumor AssaysABSTRACT
[structure: see text] The synthesis of a collection of bicyclic fused azepinones via an intramolecular beta-lactam ring-opening strategy is reported. Depending on the chirality of the various inputs, complete stereocontrol of product formation is achieved.
ABSTRACT
Pyrrolizidine benzamide (+/-)-2, the bridgehead-methyl analog of SC-53116, was prepared and evaluated for 5-HT(4) agonism activity in the rat tunica muscularis (TMM) mucosae assay. Compound (+/-)-2 has an EC(50) of 449 nM in the TMM assay, as compared to 23 nM for SC-53116, and 66 nM for the racemate of SC-53116.
