- Discovery of a Novel Potent and Selective Calcium Release-Activated Calcium Channel Inhibitor: 2,6-Difluoro- N-(2′-methyl-3′-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-[1,1′-biphenyl]-4-yl)benzamide. Structure-Activity Relationship and Preclinical Characterization
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The role of calcium release-activated calcium (CRAC) channels is well characterized and is of particular importance in T-cell function. CRAC channels are involved in the pathogenesis of several autoimmune diseases, making it an attractive therapeutic target for treating inflammatory diseases, like rheumatoid arthritis (RA). A systematic structure-activity relationship study with the goal of optimizing lipophilicity successfully yielded two lead compounds, 36 and 37. Both compounds showed decent potency and selectivity and a remarkable pharmacokinetic profile. Further characterization in in vivo RA models and subsequent histopathological evaluation of tissues led to the identification of 36 as a clinical candidate. Compound 36 displayed an excellent safety profile and had a sufficient safety margin to qualify it for use in human testing. Oral administration of 36 in Phase 1 clinical study in healthy volunteers established favorable safety, tolerability, and good target engagement as measured by levels of IL-2 and TNF-α.
- Ahirrao, Prajakta,Bakhle, Dhananjay,Bhankhede, Trupti,Bhonde, Mandar,Bokan, Sanjay,Budhe, Sagar,Dadke, Disha,Daler, Jagadeesh,Deshmukh, Gokul,George, Shaji K.,Gholve, Milind,Gundu, Jaysagar,Gupta, Rajesh,Ingawale, Sachin,Irlapatti, Nageswara Rao,Jachak, Santosh,Kalia, Anil,Kamalakannan, Prabakaran,Kamboj, Rajender Kumar,Kanoje, Vijay,Karche, Vijay,Khedkar, Nilesh Raghunath,Kizhakinagath, Praveenkumar Anidil,Kuldharan, Sandip,Kumar, Hemant,Kumar, Swaroop,Mallurwar, Sadanand,Mehta, Maneesh,Modi, Dipak,Naik, Kumar,Narasimham, Lakshmi,Nemade, Harshal Narendra,Nemmani, Kumar V. S.,Nigade, Prashant,Padiya, Kamlesh J.,Palle, Venkata P.,Pandey, Dilip,Pareek, Himani,Patil, Amit,Patil, Vinod,Pawar, Shashikant,Phukan, Samiron,Shah, Chirag,Shaikh, Zubair,Shankar, Rajesh,Sharma, Nidhi,Sharma, Sharad,Shinde, Vikas,Sindkhedkar, Milind,Singh, Minakshi,Sinha, Neelima,Tamane, Kaustubh,Venugopal, Spinvin,Vishwase, Gururaj,Wagh, Akshaya,Yeshodharan, Rajesh
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p. 17004 - 17030
(2021/12/09)
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- IMIDAZOLE DERIVATIVES AND THEIR USE AS MODULATORS OF CYCLIN DEPENDENT KINASES
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The invention provides compounds of the formula (I): and salts, tautomers, solvates and N-oxides thereof; wherein Q is CH or N; X is N, N+-O- or CR3; Y is N, N+-O- or CR3a; R1 and R2 are independently selected from hydrogen and various substituents as defined in the claims; or R1 and R2 together with the atoms to which they are attached, link to form an optionally substituted carbocyclic or heterocyclic aromatic or non-aromatic ring of 4 to 7 members; R3 is selected from hydrogen and various substituents; and R3a is selected from hydrogen and various substituents as defined in the claims. Also provided are pharmaceutical compositions containing the compounds of formula (I), processes for making the compounds and the medical uses of the compounds. The compounds of formula (I) have activity as inhibitors of CDK kinases and are useful in the treatment of inter alia proliferative diseases such as cancers.
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Page/Page column 128-129
(2010/11/17)
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- HYDROXYPHENYLSULFONAMIDES AS ANTIAPOPTOTIC BCL INHIBITORS
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The present invention provides compound of Formula (I): or a stereoisomer, tautomer, salt or solvate thereof, wherein the variables are defined herein. The compounds of formula (I) are inhibitors of Bcl-2 family antiapoptotic proteins, compositions containing the compounds and methods of treating diseases using the compounds.
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Page/Page column 62; 201-202
(2010/01/07)
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- 4,5-DIHYDRO-OXAZOL-2-YL AMINE DERIVATIVES
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The present invention relates to a compounds of formula I wherein R1, R1′, R2, R3, R4, X, Ar, and m are as defined in the specification and claims and pharmaceutically active acid addition salts thereof. Compounds of the invention have Asp2 (β-secretase, BACE 1 or Memapsin-2) inhibitory activity and are useful for the treatment of diseases characterized by elevated β-amyloid levels or β-amyloid deposits, particularly Alzheimer's disease.
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Page/Page column 36
(2009/09/05)
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- Calcium receptor modulating agents
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The present invention relates generally to compounds represented in Formula I, pharmaceutical compositions comprising them and methods of treating of diseases or disorders related to the function of the calcium sensing receptor. The invention also relates to processes for making such compounds and to intermediates useful in these processes.
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Page/Page column 44
(2008/12/08)
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