Discovery and Development of Maraviroc, a CCR5 Antagonist for the Treatment of HIV Infection

Design and Elaboration of a Tractable Tricyclic Scaffold To Synthesize Druglike Inhibitors of Dipeptidyl Peptidase-4 (DPP-4), Antagonists of the C–C Chemokine Receptor Type 5 (CCR5), and Highly Potent and Selective Phosphoinositol-3 Kinase δ (PI3Kδ) Inhibitors

“…34 CCR5 is a coreceptor for HIV entry into T cells, and maraviroc is the only marketed CCR5 receptor antagonist for R5 HIV therapy to date. 35,36 While our chemical design appears a rational "fast-follower" process, we were concerned that the tropane ring present in maraviroc had been shown to give a 40-fold increase in affinity compared to the piperidine analogue. 37 In addition, the triazole group in maraviroc adopts a conformation where it is orthogonal to the tropane ring, whereas in our proposed analogue the triazole group would be occupying a different spatial configuration.…”

“…The activation of the chemokine receptor CCR5 through its binding of endogenously expressed chemokines (macrophage inflammatory proteins MIP-1α and MIP-1β as well as “regulated on activation, normal T cell expressed, and secreted” RANTES) can cause typical cellular responses, including inhibition of cAMP production or stimulation of intracellular Ca 2+ . CCR5 is a coreceptor for HIV entry into T cells, and maraviroc is the only marketed CCR5 receptor antagonist for R5 HIV therapy to date. , …”

Development of maraviroc, a CCR5 antagonist for treatment of HIV, using a novel tropism assay

“…17 Preclinical safety studies of MVC revealed no significant safety concerns, and a phase I clinical program in healthy volunteers was initiated. 18,19 Data from these studies indicated that MVC was safe and well tolerated in doses up to 900 mg QD and 300 mg BID, did not influence the activity of major drugmetabolizing enzymes, and had an acceptable pharmacokinetic profile. 19 Phase IIa proof-of-concept studies On the basis of the favorable safety and pharmacokinetic profile of MVC demonstrated in the healthy volunteer studies, a phase IIa proof-of-concept program was initiated.…”

“…Preclinical safety studies of MVC revealed no significant safety concerns, and a phase I clinical program in healthy volunteers was initiated . Data from these studies indicated that MVC was safe and well tolerated in doses up to 900 mg QD and 300 mg BID, did not influence the activity of major drug‐metabolizing enzymes, and had an acceptable pharmacokinetic profile …”