that presented weak affinity and no antiviral activity but represented a good starting point for further optimization. compounds 1–9 in table 1 show the development of maraviroc in few steps. the chemical structure of the starting molecule (uk-107,543) is presented as compound 1. their first focus was to minimize cyp2d6 activity of the molecule and to reduce its lipophilicity. they replaced the imidazopyridine with benzimidazole and the benzhydril group was swapped out for a benzamide. the outcome was compound 2. that compound showed good binding potency and the start of an antiviral activity. further structure–activity relationship (sar) optimization of the amide region and identifying the enantiomeric preference led to the cyclobutyl amide structure in compound 3. however, the problem with the cyp2d6 activity of the compound was still unacceptable so they had to perform further sar optimization that determined that the -azabicycloamine (tropane) could replace the aminopiperidine moiety. this change in the chemical structure led to compound 4. compound 4 had no cyp2d6 activity while preserving excellent binding affinity and antiviral activity. although compound 4 showed promising results, it demonstrated 99% inhibition on the herg ion channel. that inhibition was unacceptable since it can lead to qtc interval prolongation. the research team then did a few modifications to see which part of the molecule played a role in the herg affinity. compound 5 shows an analogue that they synthesized which contained an oxygen bridgehead in the tropane ring; however, that reconstruction did not have an effect on the herg affinity. they then focused on the polar surface area in the molecule to dial out the herg affinity. these efforts resulted in compound 6. that compound preserved desired antiviral activity and was selective against the herg inhibition but the problem was its bioavailability. reduction in the lipophilicity, by replacing the benzimidazol group with a substituted triazole group gave compound 7. compound 7 had shown a significant reduction in lipophilicity and maintained the antiviral activity but again, with the introduction of a cyclobutyl group, the compound showed herg inhibition. changing the ring size in compound 7 from a cyclobutyl unit to a cyclopentyl unit in compound 8 led to a significant increase in antiviral activity and loss of herg affinity. further development led to discovery of a 4,4'-difluorocyclohexylamide also known as maraviroc. maraviroc preserved excellent antiviral activity, whilst demonstrating no significant herg binding affinity. the lack of herg binding affinity was predicted to be because of the large size of the cyclohexyl group and the high polarity of the fluoro substituents. in august 2007 the fda approved the first ccr5 antagonist, maraviroc, discovered and developed by pfizer. table 1 represents the molecular structures in the development of maraviroc.blue indicates differences from the previous step compound 1 compound 2 compound 3 compound 4 compound 5 compound 6 compound 7 compound 8 compound 9 (maraviroc) pharmacophore figure 4 predictive pharmacophore model for piperidine- and piperazine-based ccr5 antagonists the predictive pharmacophore model was developed for a large series of piperidine- and piperazine-based ccr5 antagonists by schering-plough research institute. their hypothesis consisted of mostly five features, two hydrogen bond acceptors, marked c and d in figure 4 and three hydrophobic groups, a, b and e in figure 4. part b usually has a basic nitrogen group. the model was validated using diverse set of six ccr5 antagonists from five different pharmaceutical companies. the best model correctly predicted these compounds as being highly active. it is possible to use the model as a tool in virtual screening for new small molecular ccr5 antagonists and also to predict biological activities of compounds prior to undertaking their costly synthesis. binding figure 5. putative binding of aplaviroc to the ccr5 receptor figure 6. putative binding of maraviroc to the ccr5 receptor ccr5 is a member of g protein-coupled, seven transmembrane segment receptors. the structure of the receptor comprises seven-helix bundle in the transmembrane region, these regions are labeled i–vii in figures 5 and 6. the ccr5 antagonists are predicted to bind to a putative binding pocket which is buried inside the transmembrane domain, enclosed by the seven transmembrane helices. the binding pocket is very hydrophobic with multiple aromatic residues lining the pocket. the key residues are tryptophan 86 and 248 (trp86, trp248), tyrosine 108 and 251 (tyr108, tyr251), phenylalanine 109 (phe109), threonine 195 (thr195), isoleucine 198 (ile198), glutamic acid 283 (glu283). ccr5 antagonists are very different in shape and electrostatic potential although they all share the same binding pocket. the interesting thing about the binding of these molecules is that they exhibit significantly different binding modes, although they all establish an extensive interaction network with ccr5. aplaviroc the putative binding mode for aplaviroc is shown in figure 5. the key saltbridge interaction between aplaviroc and glu283 is predicted to be quite weak compared to other ccr5 antagonists. the hydroxyl group on aplaviroc forms a strong hydrogen bond to the polar residue thr195. this h-bond interaction is the strongest with aplaviroc compared to other ccr5 antagonists. the cyclohexyl group in the aplaviroc structure is predicted to interact with the receptor in a hydrophobic pocket formed by ile198, thr195 and phe109 and is thought to show quite strong hydrophobic interactions. the researchers predict that the butyl group of aplaviroc is buried within the helical bundle through strong hydrophobic interaction with multiple aromatic residues of the ccr5 receptor. aplaviroc has a unique feature of preserving two of the natural chemokine protein ligands binding to ccr5 and subsequent activation, whereas maraviroc and the other antagonists almost fully block chemokine-ccr5 interactions. this kind of interference is so far considered to be safe, and individuals that naturally lack ccr5 do not show any obvious health problems. however, to limit the toxicity and side effects of ccr5 antagonists it would be ideal to be able to preserve the chemokine receptor function. consequently, it should be of interest to design inhibitors that specifically disrupt ccr5–gp120 binding but do not affect the ccr5 chemokine activation. maraviroc the putative binding mode for maraviroc is shown in figure 6. the strongest interaction is estimated to be between maraviroc and glutamic acid (glu283) through a strong salt bridge interaction. the interaction between tryptophan (trp86) and maraviroc involves t-shaped π-π stacking while the interaction with phenylalanine (phe109) is predicted to be hydrophobic. tyrosine (tyr108) is thought to interact with the phenyl group on maraviroc through a parallel displaced interaction. the interaction between maraviroc and isoleucine (ile198) is predicted to be mostly hydrophobic in nature and the interaction between maraviroc and tyrosine (tyr251) is very limited. other ccr5 antagonists figure 7. molecular structure of compound a development of new ccr5 antagonists continues, both for their antiviral effects and also for potential utility in a variety of autoimmune indications. researchers at roche palo alto discovered a novel series of potent ccr5 small-molecule antagonists. lead optimization was pursued by balancing opposing trends of metabolic stability and potency. combination of the spiropiperidine template with pharmacophore elements from both aplaviroc, and schering's ccr5 antagonist program, led to the initial lead compound in this series. further development of that lead compound led to the discovery of compound a in figure 7 — a compound that possesses a good selectivity and pharmacokinetic properties. the ccr5 antagonist incb009471 has nanomolar activity against hiv-1 in vitro. this compound demonstrated potent and prolonged antiviral activity against r5-tropic hiv-1 when given 200 mg once daily dose for 14 days. these findings supported further clinical development of incb009471 and they have since progressed to phase iib clinical trials. as of 2009 the study of this compound is inactive and no further studies are planned at this time. not only small molecules but also proteins delivered by gene therapy have been suggested to ablate ccr5 function, an approach that has also been employed for other hiv targets.