Arthur V. Miller

2-Arylbenzoxazoles as novel cholesteryl ester transfer protein inhibitors: optimization via array synthesis.

2-Arylbenzoxazole 5 was identified as a hit from a fluorescence-based high-throughput screen for CETP inhibitors. The synthesis and SAR investigation employing array synthesis of the A- and B-rings are described.

Diphenylpyridylethanamine (DPPE) derivatives as cholesteryl ester transfer protein (CETP) inhibitors.

A series of diphenylpyridylethanamine (DPPE) derivatives was identified exhibiting potent CETP inhibition. Replacing the labile ester functionality in the initial lead 7 generated a series of amides and ureas. Further optimization of the DPPE series for potency resulted in the discovery of cyclopentylurea 15d, which demonstrated a reduction in cholesterol ester transfer activity (48% of predose level) in hCETP/apoB-100 dual transgenic mice. The PK profile of 15d was suboptimal, and further optimization of the N-terminus resulted in the discovery of amide 20 with an improved PK profile and robust efficacy in transgenic hCETP/apoB-100 mice and in hamsters. Compound 20 demonstrated no significant changes in either mean arterial blood pressure or heart rate in telemeterized rats despite sustained high exposures.

Benzothiadiazine dioxides: A new class of potent angiotensin-II (AT1) receptor antagonists

Abstract N-Biphenylmethyl benzothiadiazine dioxides were prepared as potential angiotensin-II receptor antagonists. Stability of the compounds is dependent upon the nature of the substituent at position 3 of the benzothiadiazine ring, while potency is dependent upon the nature of substitution in the benzo fused ring. 3-(Propylthio)-4-[2′-(2H-tetrazol-5-yl)[1,1′-biphenyl]-4-ylmethyl]-4H-1,2,4-benzothiadiazine-6-carboxylic acid, 1,1-dioxide ( 17 ) is one of the most potent examples, with functional activity (K B ) below 01 nM.

Pyrrolo[1,2-f]triazines as JAK2 inhibitors: Achieving potency and selectivity for JAK2 over JAK3.

SAR studies of pyrrolo[1,2-f]triazines as JAK2 inhibitors is presented. Achieving JAK2 inhibition selectively over JAK3 is discussed.

Synthesis of N-Alkyl-1,2,4-oxadiazinones as Angiotensin-II (AT1) Receptor Antagonists

4-Alkyl-1,2,4-oxadiazinones were prepared by regiospecific alkylation of the corresponding 4H-oxadiazinones, which were synthesized by a trimethylaluminium mediated cyclization reaction. Alkylation was regiospecific and generally facile; in one example, however, an unusual fragmentation reaction occurred. A homochiral oxadiazineone was also prepared and alkylated under the described conditions. 4-Biphenylmethyl-1,2,4-oxadi-azinones were potent angiotensin-II receptor antagonists

Synthesis of 4-(N-alkyl-N-heteroaryl)amino-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile derivatives via an unusual 1,4-oxygen to nitrogen heteroaryl migration

Abstract Various heteroaryls were found to undergo 1,4-oxygen to nitrogen migration (e.g. 4→1 ) under acidic conditions. This unprecedented migratin provides a convenient access to 4-(N-alkyl-N-heteroaryl)amino-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile derivatives, which are otherwise difficult to prepare.