Richard J. Budhu

Antagonists of the human CCR5 receptor as anti-HIV-1 agents. Part 1: Discovery and initial structure–activity relationships for 1-amino-2-phenyl-4-(piperidin-1-yl)butanes

Screening of the Merck sample collection for compounds with CCR5 receptor binding afforded (2S)-2-(3,4-dichlorophenyl)-1-[N-(methyl)-N-(phenylsulfonyl)amino]-4-[spiro(2,3-dihydrobenzthiophene-3,4-piperidin-1-yl)]butane S-oxide (4) as a potent lead structure having an IC50 binding affinity of 35 nM. Herein, we describe the discovery of this lead structure and our initial structure activity relationship studies directed toward the requirement for and optimization of the 1-amino fragment.

1,3,4-Trisubstituted pyrrolidine CCR5 receptor antagonists. Part 2: lead optimization affording selective, orally bioavailable compounds with potent anti-HIV activity.

Investigations of the structure-activity relationships of 1,3,4-trisubstituted pyrrolidine human CCR5 receptor antagonists afforded orally bioavailable compounds with the ability to inhibit HIV replication in vitro.

1,3,4-Trisubstituted pyrrolidine CCR5 receptor antagonists. Part 1: discovery of the pyrrolidine scaffold and determination of its stereochemical requirements.

A series of 1,3,4-trisubstituted pyrrolidines was discovered to have the ability to displace [(125)I]-MIP-1alpha from the CCR5 receptor expressed on Chinese hamster ovary (CHO) cell membranes. CCR5 activity was found to be dependent on the regiochemistry and the absolute stereochemistry of the pyrrolidine.

1,3,4-Trisubstituted pyrrolidine CCR5 receptor antagonists. Part 4: Synthesis of N-1 acidic functionality affording analogues with enhanced antiviral activity against HIV

A series of alpha-(pyrrolidin-1-yl)acetic acids is presented as selective and potent antivirals against HIV. Several of the pyrrolidine zwitterions demonstrated reasonable in vitro properties, enhanced antiviral activities and improved pharmacokinetic profiles over pyrrolidine 1.

1,3,4-Trisubstituted pyrrolidine CCR5 receptor antagonists: modifications of the arylpropylpiperidine side chains.

The 4-(3-phenylprop-1-yl)piperidine moiety of the 1,3,4-trisubstituted pyrrolidine CCR5 antagonist 1 was modified with electron deficient aromatics as well as replacement of the benzylic methylene with sulfones, gem-difluoromethylenes and alcohols in an effort to balance the antiviral potency with reasonable pharmacokinetics.

1,3,4 trisubstituted pyrrolidine CCR5 receptor antagonists bearing 4-aminoheterocycle substituted piperidine side chains

A new class of 4-(aminoheterocycle)piperidine derived 1,3,4 trisubstituted pyrrolidine CCR5 antagonists is reported. Compound 4a is shown to have good binding affinity (1.8 nM) and antiviral activity in PBMCs (IC(95)=50 nM). Compound 4a also has improved PK properties relative to 1.

1,3,4-Trisubstituted pyrrolidine CCR5 receptor antagonists. Part 3: polar functionality and its effect on anti-HIV-1 activity.

Incorporation of acidic functional groups into a lead CCR5 antagonist identified from a targeted combinatorial library resulted in compounds with enhanced anti-HIV-1 activity and attenuated L-type calcium channel affinity.

1,4-diacylpiperazine-2-(S)-[(N-aminoalkyl)carboxamides] as novel, potent substance P receptor antagonists

Abstract A series of N,N′-diacylpiperazine-2-carboxamides are shown to be antagonists of the NK-1 (Substance P) receptor. Elaboration of the C2 sidechain with aminoalkyl groups leads to two series of potent antagonists, one containing simple dialkylamino groups and the second featuring 2-methoxybenzylamino derivatives with divergent SARs with respect to substitution at the C2 amide bond.

1,2,3-Trisubstituted cyclohexyl substance P antagonists: Significance of the ring nitrogen in piperidine-based NK-1 receptor antagonists

Abstract A stereocontrolled synthesis of 1-benzyloxy-2-phenylcyclohexane derivatives containing polar substituents at C3 is described. These compounds, designed to test the role of the ring nitrogen in a related series of potent piperidine-based substance P antagonists, show similar NK-1 receptor affinity, indicating that the nitrogen may serve a largely structural role in N-substituted piperidine antagonists.